Aminoalcohol derivatives

ABSTRACT

The present invention relates to a compound formula (I) wherein X 1  is bond or —O—CH 2 —, (II) or (III) R 1  is hydrogen or an amino protective group, a is phenyl, indolyl or carbazolyl, each of which may be substituted with one or two substituent(s), and B is hydrogen; halogen; lower alkyl; lower alkoxycarbonyl; cyclo(lower)alkyl; or a heterocyclic group, naphthyl, 1,2,3,4-tetrahydronaphthyl, benzyl or phenyl, each of which may be substituted with one or two substituent(s), or a salt thereof. The compound (I) of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of pollakiures or urinary incontinence.

TECHNICAL FIELD

[0001] This invention relates to new aminoalcohol derivatives and saltsthereof which are beta-3 (β₃) adrenergic receptor agonists and useful asa medicament.

DISCLOSURE OF INVENTION

[0002] This invention relates to new aminoalcohol derivatives which areβ₃ adrenergic receptor agonists and salts thereof.

[0003] More particularly, it relates to new aminoalcohol derivatives andsalts thereof which have gut sympathomimetic, anti-ulcerous,anti-pancreatitis, lipolytic, anti-urinary incontinence,anti-pollakiuria activities, anti-diabetes and anti-obesity, toprocesses for the preparation thereof, to a pharmaceutical compositioncomprising the same and to a method of using the same therapeutically inthe treatment and/or prevention of gastro-intestinal disorders caused bysmooth muscle contractions in human beings or animal.

[0004] One object of this invention is to provide new and usefulaminoalcohol derivatives and salts thereof which have gutsympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence,anti-pollakiuria activities, anti-diabetes and anti-obesity.

[0005] Another object of this invention is to provide processes for thepreparation of said aminoalcohol derivatives and salts thereof.

[0006] A further object of this invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said aminoalcoholderivatives and salts thereof.

[0007] Still further object of this invention is to provide atherapeutical method for the treatment and/or prevention of aforesaiddiseases in human beings or animals, using said aminoalcohol derivativesand salts thereof.

[0008] The object aminoalcohol derivatives of this invention are new andcan be represented by the following formula [I]:

[0009] wherein

[0010] X₁ is bond or —O—CH₂—,

[0011] (in which R² is hydrogen or lower alkyl and n is an integer of 1or 2)

[0012] [in which

[0013] (in which R³ is hydrogen or lower alkyl),

[0014] (in which R⁴ is hydrogen or lower alkyl),

[0015] (in which Y₂ is lower alkylene)],

[0016] R¹ is hydrogen or an amino protective group,

[0017] A is phenyl, indolyl or carbazolyl, each of which may besubstituted with one or two substituent(s) selected from the groupconsisting of halogen, hydroxy, hydroxy(lower)alkyl and benzyloxy, and

[0018] B is hydrogen; halogen; lower alkyl; lower alkoxycarbonyl;cyclo(lower)alkyl; or a heterocyclic group, naphthyl,1,2,3,4-tetrahydronaphthyl, benzyl or phenyl, each of which may besubstituted with one or two substituent(s) selected from the groupconsisting of halogen, lower alkoxy, mono(or di ortri)halo(lower)alkoxy, carboxy(lower)alkoxy, loweralkoxycarbonyl(lower)alkoxy, phenoxy, lower alkyl, mono(or di ortri)-halo(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, loweralkanoyl, benzoyl, mono(or di)(lower)-alkylcarbamoyl, (loweralkylsulfonyl)carbamoyl, (lower alkylsulfonyl)amino, (loweralkoxycarbonyl)amino, amino, nitro, pyridyl, triazolyl, thiazolyloptionally substituted with phenyl or lower alkyl, and phenyl optionallysubstituted with mono(or di or tri)halo(lower)alkyl,

[0019] or a salt thereof.

[0020] The object compound [I] or a salt thereof can be prepared by thefollowing processes.

[0021] wherein

[0022] X₁, X₂, R¹, A and B are each as defined above,

[0023] R_(a) ¹ is an amino protective group, a

[0024] R_(a) ² is lower alkyl, a

[0025] W₁ is a leaving group,

[0026] W₂ is an acid residue,

[0027] m is an integer of 1 or 2, k is 0 or an integer of 1, and

[0028] {circle over (P)} is polymer.

[0029] In the above and subsequent description of the presentspecification, suitable examples of the various definition to beincluded within the scope of the invention are explained in detail inthe following.

[0030] The term “lower” is intended to mean a group having 1 to 6,preferably 1 to 4, carbon atom(s), unless otherewise provided.

[0031] Suitable example of “lower alkyl” and “lower alkyl” moiety in theterms of “hydroxy(lower)alkyl”, “mono(or di or tri)halo(lower)alkyl”,etc. may include straight or branched one having 1 to 6 carbon atom(s),such as methyl, ethyl propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl,isohexyl, and the like.

[0032] Suitable “lower alkoxy” and “lower alkoxy” moiety in the terms of“lower alkoxycarbonyl”, “carboxy(lower)alkoxy”, etc. may be a straightor branched one such as methoxy, ethoxy, propoxy, isopropoxy,1-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy,neopentyloxy, tert-pentyloxy, hexyloxy, and the like, in which thepreferred one may be C₁-C₄ alkoxy, and the most preferred one may bemethoxy or ethoxy.

[0033] Suitable “lower alkylene” may include straight or branched onesuch as methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, methylmethylene, ethylethylene,propylene, and the like, in which more preferable example may be C₁-C₄alkylene and the most preferable one may be trimethylene.

[0034] Suitable example of “halogen” may be fluoro, chloro, bromo andiodo.

[0035] Suitable “cyclo(lower)alkyl” may include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl, in which the preferred one may becyclohexyl.

[0036] Suitable “lower alkanoyl” may be formyl, acetyl, propanoyl,butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyland the like, in which the preferred one may be acetyl.

[0037] Suitable “mono(or di or tri)halo(lower)alkyl” may befluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl,tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or2-chloroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and the like, inwhich the preferred one may be trifluoromethyl.

[0038] Suitable example of “heterocyclic group” may include

[0039] unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;

[0040] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;

[0041] unsaturated condensed heterocyclic group containing 1 to 4nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indazolyl,benzotriazolyl, etc.;

[0042] unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

[0043] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

[0044] unsaturated condensed heterocyclic group containing 1 or 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

[0045] unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

[0046] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

[0047] unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 or 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;

[0048] unsaturated condensed heterocyclic group containing 1 or 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, imidazothiadiazolyl, etc.;

[0049] unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example, furyl,etc.;

[0050] saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom, for example,tetrahydrofuran, tetrahydropyran, etc.;

[0051] unsaturated condensed heterocyclic group containing 1 or 2 oxygenatom(s), for example, benzofuranyl, etc.;

[0052] unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 or 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

[0053] unsaturated condensed heterocyclic group containing 1 or 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

[0054] unsaturated condensed heterocyclic group containing an oxygenatom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl, etc.;2-oxo-2,3-dihydro-1H-benzimidazolyl; and the like.

[0055] Suitable example of “polymer” may be polystyrene which may beused for a solid phase support linkage method mentioned below.

[0056] Suitable “leaving group” may include hydroxy, reactive groupderived from hydroxy and the like.

[0057] Suitable “reactive group derived from hydroxy” may include anacid residue and the like.

[0058] Suitable “acid residue” may include halogen (e.g. fluoro, chloro,bromo, iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and thelike.

[0059] Suitable example of “amino protective group” moiety may be commonamino protective group such as acyl, for example, substituted orunsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl,trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g.tert-butoxycarbonyl, tert-amyloxy-carbonyl, etc.], substituted orunsubstituted aralkyloxy-carbonyl [e.g. benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstitutedarenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl,ar(lower)alkyl [e.g. trityl, benzyl, etc.], and the like, in whichpreferable one is phenyl(lower)alkyl such as benzyl.

[0060] Suitable salts of the object aminoalcohol derivative [I] arepharmaceutically acceptable salts and include conventional non-toxicsalts such as an inorganic acid addition salt [e.g. hydrochloride,hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt[e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate,tartarate, citrate, methanesulfonate, benzenesulfonate,toluenesulfonate, etc.] or the like.

[0061] The Processes 1 to 5 for preparing the object compound [I] of thepresent invention are explained in detail in the following.

[0062] Process 1

[0063] The object compound [I] or a salt thereof can be prepared byreacting a compound [II] or a salt thereof with a compound [III] or asalt thereof.

[0064] Suitable salt of the compounds [II] and [III] may be the same asthose exemplified for the compound [I].

[0065] The reaction is preferably carried out in the presence of a basesuch as an alkali metal carbonate [e.g. sodium carbonate, potassiumcarbonate, etc.], an alkaline earth metal carbonate [e.g. magnesiumcarbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g.sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine[e.g. trimethylamine, triethylamine, etc.], picoline or the like.

[0066] The reaction is usually carried out in a conventional solvent,such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol,etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organicsolvent which does not adversely influence the reaction.

[0067] The reaction temperature is not critical, and the reaction can becarried out under cooling to heating.

[0068] Process 2

[0069] The object compound [Ib] or a salt thereof can be prepared bysubjecting a compound [Ia] or a salt thereof to elimination reaction ofthe amino protective group.

[0070] Suitable salts of the compounds [Ia] and [Ib] may be the same asthose exemplified for the compound [I].

[0071] This reaction can be carried out in the manner disclosed inExamples 2 or 11.

[0072] Process 3

[0073] The object compound [Ic] or a salt thereof can be prepared byreacting the compound [IV] or a salt thereof with the compound [V] or asalt thereof.

[0074] Suitable salt of the compounds [Ic], [V] and [IV] may be the sameas those exemplified for the compound [I].

[0075] This reaction is usually carried out in a solvent such as alcohol[e.g. methanol, ethanol, etc.], dichloromethane, benzene,N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any othersolvent which does not adversely affect the reaction.

[0076] The reaction may be carried out in the presence of an inorganicor an organic base such as an alkali metal hydroxide [e.g. sodiumhydroxide, potassium hydroxide, etc.], an alkali metal carbonate [e.g.sodium carbonate, potassium carbonate, etc.], an alkali metalbicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.],alkali metal hydride [e.g. sodium hydride, potassium hydride, etc.],tri(lower)alkylamine [e.g. trimethylamine, triethylamine,diisopropylethylamine, etc.], pyridine or its derivative [e.g. picoline,lutidine, 4-dimethylaminopyridine, etc.], or the like. In case that thebase to be used in liquid, it can also be used as a solvent.

[0077] This reaction can be also carried out in the manner disclosed inExample 60, 61 or 62 or similar manners thereto.

[0078] The reaction temperature is not critical, and the reaction can becarried out under cooling, at room temperature or under warming orheating.

[0079] Process 4

[0080] The object compound [Ie] or a salt thereof can be prepared byreacting the compound [Id] or a salt thereof with the compound [VI].

[0081] Suitable salt of the compound [Id] and [Ie] may be the same asthose exemplified for the compound [I].

[0082] This reaction is usually carried out in a conventional solventsuch as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, dichloromethane, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,N,N-dimethylacetamide, pyridine or any other organic solvent which doesnot adversely influence the reaction.

[0083] The reaction temperature is not critical, and the reaction isusually carried out under cooling to warming.

[0084] The reaction may also be carried out in the presence of aninorganic or organic base such as an alkali metal bicarbonate,tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine,N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.

[0085] Process 5

[0086] The object compound [If] or a salt thereof can be prepared bysubjecting the compound [IV] or a salt thereof with the compound [VII]or a salt thereof.

[0087] Suitable salts of the compounds [If], [IV] and [VII] may be thesame as those exemplified for the compound [I].

[0088] This reaction can be carried out in the manner disclosed inExample 1 or 3 or similar manners thereto.

[0089] This reaction can be also carried out in the manner disclosed inExample 64 or 66 or similar manners thereto.

[0090] Process 6

[0091] The object compound [Ic] or a salt thereof can be prepared bymeans of a solid phase support linkage method, namely by reacting acompound [VIII] with compound [IX] or a salt thereof and then byreacting the resultant compound [α]with a compound [IV] or a saltthereof.

[0092] Suitable salt of the compounds [Ic], [IV], [VIII], [IX] and[α]may be the same as those exemplified for the compound [I].

[0093] This reaction can be carried out in the manner disclosed inExample 59 or similar manner thereto.

[0094] The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like,and converted to the desired salt in conventional manners, if necessary.

[0095] It is to be noted that the compound [I] and the other compoundsmay include one or more stereoisomers due to asymmetric carbon atoms,and all of such isomers and mixture thereof are included within thescope of this invention.

[0096] It is further to be noted that isomerization or rearrangement ofthe object compound [I] may occur due to the effect of the light, acid,base or the like, and the compound obtained as the result of saidisomerization or rearrangement is also included within the scope of thepresent invention.

[0097] It is also to be noted that the solvating form of the compound[I] (e.g. hydrate, etc.) and any form of the crystal of the compound [I]are included within the scope of the present invention.

[0098] The object compound [I] or a salt thereof possesses gutsympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic,anti-urinary incontinence and anti-pollakiuria activities, and areuseful for the treatment and/or prevention of gastro-intestinaldisorders caused by smooth muscle contractions in human beings oranimals, and more particularly for the treatment and/or prevention ofspasm or hyperanakinesia in case of irritable bowel syndrome, gastritis,gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis,urinary calculus and the like; for the treatment and/or prevention ofulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causedby non steroidal anti-inflammatory drugs, or the like; for the treatmentand/or prevention of dysuria such as pollakiuria, urinary incontinenceor the like in case of nervous pollakiuria, neurogenic bladderdysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis,chronic prostatitis, prostatic hypertrophy or the like; for thetreatment and/or prevention of pancreatitis, obesity, diabetes,glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma,melancholia, depression or the like; for the treatment and/or preventionof diseases as the result of insulin resistance (e.g. hypertension,hyperinsulinemia, etc.); for the treatment and/or prevention ofneurogenetic inflammation; and for reducing a wasting condition, and thelike.

[0099] Additionally, β₃ adrenergic receptor agonists are known to lowertriglyceride and cholesterol levels and to raise high densitylipoprotein levels in mammals (U.S. Pat. No. 5,451,677). Accordingly,the object compound [I] is useful in the treatment and/or prevention ofconditions such as hyper-triglyceridaemia, hypercholesterolaemia and inlowering high density lipoprotein levels as well as in the treatment ofatherosclerotic and cardiovascular diseases and related conditions.

[0100] Moreover, the object compound [I] is useful for inhibitinguterine contractions, preventing premature labor, and treating andpreventing dysmenorrhea.

[0101] In order to show the usefulness of the compound [I] for theprophylactic and therapeutic treatment of above-mentioned disease inhuman beings or animals, the pharmacological test data of arepresentative compound thereof are shown in the following.

[0102] Test

[0103] Effect on the increase in intravesical pressure induced bycarbachol in anesthetized dog

[0104] Test Compound

[0105] (1)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]phenyl]-1H-pyrrole-2-carboxamide

[0106] Test Method

[0107] Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hoursand maintained under halothane anesthesia. A 12F Foley catheter waslubricated with water soluble jelly, inserted into the urethral orificeand advanced approximately 10 cm until the balloon tip was placed wellinside the bladder. The balloon was then inflated with 5 ml of room airand catheter slowly withdrawn just part the first resistance that isfelt at the bladder neck. Urine was completely drained out through thecatheter, and 30 ml of biological saline was infused. The catheter wasconnected to pressure transducer, and intravesical pressure wascontinuously recorded. The test compound was injected by intra-duodenaroute at 30 minutes before the administration of carbachol (1.8 μg/kg).Test Results Treatment Increase in intravesical pressure (mmHg) Control7.0 ± 1.0 Test Compound (1)  2.6 ± 0.05 (0.32 mg/kg)

[0108] Preferred embodiments of the object compound [I] are as follow:X₁ is bond or —O—CH₂—,

[0109] (in which R² is hydrogen or lower alkyl (more preferably C₁-C₄alkyl, most preferably methyl) and n is an integer of 1 or 2)

[0110] (in which Y₁ is

[0111] (in which R³ is hydrogen or lower alkyl (more preferably C₁-C₄alkyl, most preferably methyl)),

[0112] (in which R⁴ is hydrogen or lower alkyl (more preferably C₁-C₄alkyl, most preferably methyl)), —CH₂CH₂—, —CH═CH— or

[0113] (in which Y₂ is lower alkylene (more preferably C₂-C₄ alkylene,most preferably trimethylene))],

[0114] R¹ is hydrogen,

[0115] A is phenyl which may be substituted with one or twosubstituent(s) selected from the group consisting of halogen, hydroxy,hydroxy(lower)alkyl (more preferably hydroxy(C₁-C₄)alkyl, mostpreferably hydroxymethyl) or benzyloxy,

[0116] B is pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,piperidyl, indolyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,cinnolinyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl,benzofuranyl, benzothienyl, naphthyl, benzyl or phenyl, each of whichmay be substituted with one or two substituent(s) selected from thegroup consisting of halogen (more preferably fluoro or chloro), loweralkoxy (more preferably C₁-C₄ alkoxy, most preferably methoxy), mono(ordi or tri)halo(lower)alkoxy (more preferably mono(or di ortri)(C₁-C₄)alkoxy, most preferably trifluoromethoxy),carboxy(lower)alkoxy (more preferably carboxy(C₁-C₄)alkoxy, mostpreferably carboxymethoxy), lower alkoxycarbonyl(lower)alkoxy (morepreferably C₁-C₄ alkoxycarbonyl(C₁-C₄)alkoxy, most preferablyethoxycarbonylmethoxy), phenoxy, lower alkyl (more preferably C₁-C₄alkyl, most preferably methyl), mono(or di or tri)halo(lower)alkyl (morepreferably mono(or di or tri)halo(C₁-C₄)alkyl, most preferablytrifluoromethyl), cyano, carboxy, lower alkoxycarbonyl (more preferablyC₁-C₄ alkoxycarbonyl, most preferably ethoxycarbonyl), lower alkanoyl(more preferably C₁-C₄ alkanoyl, most preferably acetyl), benzoyl,mono(or di)(lower)alkylcarbamoyl (more preferably mono(ordi)(C₁-C₄)alkylcarbamoyl, most preferably dimethylcarbamoyl), (loweralkylsulfonyl)carbamoyl(more preferably (C₁-C₄ alkylsulfonyl)carbamoyl,most preferably (methanesulfonyl)carbamoyl), (lower alkylsulfonyl)amino(more preferably (C₁-C₄ alkylsulfonyl)amino, most preferably(methanesulfonyl)amino), (lower alkoxycarbonyl)amino (more preferably(C₁-C₄ alkoxycarbonyl)amino, most preferably (methoxycarbonyl)amino),amino, nitro, pyridyl, triazolyl, thiazolyl optionally substituted withphenyl or lower alkyl (more preferably C₁-C₄ alkyl, most preferablymethyl), and phenyl optionally substituted with mono(or di ortri)halo(lower)alkyl (more preferably mono(or di ortri)halo(C₁-C₄)alkyl, most preferably trifluoromethyl).

[0117] More preferred embodiments of the object compound [I] are asfollow:

[0118] X₁ is —O—CH₂

[0119] (in which R² is hydrogen and n is an integer of 1) or

[0120] R¹ is hydrogen,

[0121] A is phenyl which may be substituted with one or twosubstituent(s) selected from the group consisting of halogen, hydroxy,hydroxy(lower)alkyl and benzyloxy,

[0122] B is pyrrolyl, pyridyl, naphthyl or phenyl, each of which may besubstituted with one or two substituent(s) selected from the groupconsisting of halogen, lower alkoxy, carboxy(lower)alkoxy, loweralkoxycarbonyl-(lower)alkoxy, lower alkyl, mono(or di ortri)halo-(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, loweralkanoyl, mono(or di) (lower)alkylcarbamoyl, (loweralkylsulfonyl)carbamoyl, (lower alkylsulfonyl)-amino, (loweralkoxycarbonyl)amino and nitro.

[0123] The following Preparations and Examples are given for the purposeof illustrating this invention.

[0124] Preparation 1

[0125] A mixture of (2S)-2-(phenoxymethyl)oxirane (2.30 g),(2S)-2-amino-3-(4-nitrophenyl)-1-propanol (3.0 g) and ethanol (30 ml)was heated under reflux for 18 hours. The reaction mixture wasevaporated in vacuo. The residue was triturated with ethyl acetate togive(2S)-3-(4-nitrophenyl)-2-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-1-propanol(3.97 g) as a pale yellow powder. This powder was used for the next stepwithout further purification.

[0126] Preparation 2

[0127] A mixture of(2S)-3-(4-nitrophenyl)-2-[((2S)-2-hydroxy-3-phenoxypropyl)amino]-1-propanol(3.97 g), di-tert-butyl dicarbonate (3.0 g) and tetrahydrofuran (40 ml)was stirred at room temperature for 20 hours. The reaction mixture wasevaporated in vacuo. The residue was triturated with ether to givetert-butylN-[(1S)-2-hydroxy-1-(4-nitrobenzyl)-ethyl]-N-((2S)-2-hydroxy-3-phenoxypropyl)carbamate(4.39 g) as a white powder.

[0128] NMR (CDCl₃, δ): 1.62 (9H, s), 2.15-4.20 (10H, m), 6.78-7.22 (7H,m), 8.18 (2H, d, J=8 Hz)

[0129] Preparation 3

[0130] A mixture of tert-butylN-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl)-N-((2S)-2-hydroxy-3-phenoxypropyl)-carbamate(4.29 g), 10% palladium on carbon (50% wet, 429 mg), methanol (43 ml)and tetrahydrofuran (22 ml) was stirred at room temperature underhydrogen atmosphere (1 atm) for 4 hours. The catalyst was removed byvacuum filtration through celite and rinsed with methanol. The filtrateand washings were combined and evaporated in vacuo to give a colorlessoil (4.19 g). The residue was purified by a silica gel columnchromatography (silica gel 250 g, eluting with hexane:ethyl acetate=1:1)to give the first crop of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropyl)carbamate(2.85 g) as a colorless syrup and the second crop (527 mg) as acolorless syrup.

[0131] NMR (CDCl₃, δ): 1.48 (9H, s), 2.40-4.40 (10H, m), 6.62 (2H, d,J=8 Hz), 6.8-7.40 (7H, m)

[0132] Preparation 4

[0133] A mixture of (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (15.0 g),di-tert-butyl dicarbonate 4(20.0 g) and tetrahydrofuran (120 ml) wasstirred at room temperature for 1.5 hours. The reaction mixture wasevaporated in vacuo. The residue was triturated with ether to givetert-butyl N-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (19.82 g)as a white powder.

[0134] NMR (CDCl₃, δ): 1.40 (9H, s), 2.16 (1H, t, J=4 Hz), 2.98 (2H, d,J=6 Hz), 3.50-3.78 (2H, m), 3.90 (1H, m), 4.82 (1H, d, J=6 Hz), 7.41(2H, d, J=8 Hz), 8.18 (2H, d, J=8 Hz)

[0135] Preparation 5

[0136] A mixture of tert-butylN-[(1S)-2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (22.3 g),2,2-dimethoxypropane (46.3 ml), p-toluenesulfonic acid monohydrate (1.43g) and dichloromethane (200 ml) was stirred at room temperature for 15hours. The reaction mixture was washed with saturated aqueous sodiumbicarbonate and brine, dried over magnesium sulfate and evaporated invacuo. The residue was triturated with isopropyl ether to givetert-butyl(S)-4-(4-nitrobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (16.9g) as a pale yellow powder.

[0137] NMR (CDCl₃, δ): 1.42-1.68 (15H, m), 2.84 (1H, dd, J=15, 10 Hz),3.26 (1H, br), 3.72 (1H, d, J=10 Hz), 3.86 (1H, dd, J=10, 7 Hz), 4.10(1H, br), 7.40 (2H, br), 8.20 (2H, br)

[0138] Preparation 6

[0139] A mixture of tert-butyl(S)-4-(4-nitrobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (22.25g), 10% palladium on carbon (50% wet, 2.23 g) methanol (223 ml) andtetrahydrofuran (112 ml) was stirred at room temperature under hydrogenatmosphere (4 atm) for 1.5 hours. The catalyst was removed by vacuumfiltration through celite and rinsed with methanol. The filtrate andwashings were combined and evaporated in vacuo to give a colorless oil(20.82 g). The residue was purified by a silica gel columnchromatography (silica gel 250 g, elution with hexane:ethyl acetate=3:1)to give tert-butyl(S)-4-(4-aminobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate as apale yellow syrup (19.43 g).

[0140] NMR (CDCl₃, δ): 1.40-1.68 (15H, m), 2.66 (1H, dd, J=12, 1 Hz),3.06 (1H, br), 3.50-4.04 (3H, m), 7.62 (2H, br d, J=8 Hz), 7.02 (2H, br)

[0141] Preparation 7

[0142] A suspension of (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (5.89g) and benzaldehyde (3.39 g) in dichloromethane (59 ml) was stirred atroom temperature for 2.5 hours. The mixture was evaporated, and theresidual solid was suspended in ethanol (47 ml)-dichloromethane (11.8ml). Sodium borohydride (1.25 g) was slowly added to the suspension, andthe mixture was stirred at room temperature for 5 hours. The mixture waspoured onto water (47 ml) and stirred at room temperature for 15minutes. The precipitate formed was collected by filtration, washed withwater, and dried in vacuo. The crude product was recrystallized fromethanol to give (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (5.18g) as a pale yellow powder. The filtrates obtained above were combined,concentrated, and partitioned between chloroform and water. The organiclayer was separated, washed successively with water and brine, driedover magnesium sulfate, and filtered. The filtrate was concentrated andthe residue was purified by column chromatography (silica gel,chloroform/methanol) to give the additional amount of product (2.78 g)as a white powder.

[0143] NMR (CDCl₃, δ): 2.72-3.12 (3H, m), 3.35 (1H, dd, J=11 and 4 Hz),3.64 (1H, dd, J=11 and 4 Hz), 3.80 (2H, s), 7.08-7.48 (7H, m), 8.14 (2H,d, J=9 Hz)

[0144] MS m/z: 287 (M⁺+1)

[0145] Preparation 8

[0146] A mixture of (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol(1.15 g) and (2S)-2-(phenoxymethyl)oxirane (661 mg) in ethanol (9.2 ml)was heated to reflux for 3 hours. After allowed to cool to roomtemperature, the mixture was concentrated and the residue was purifiedby column chromatography (silica gel, hexane/ethyl acetate) to give(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl)amino]-3-(4-nitrophenyl)-1-propanol(1.17 g) as a pale yellow solid.

[0147] NMR (CDCl₃, δ): 2.60-3.12 (4H, m), 3.12-3.32 (1H, m), 3.40-3.75(3H, m), 3.75-4.08 (4H, m), 6.84 (2H, d, J=9 Hz), 6.90-7.02 (1H, m),7.10-7.40 (9H, m), 8.11 (2H, d, J=9 Hz)

[0148] MS m/z: 437 (M⁺+1)

[0149] Preparation 9

[0150] To a suspension of(2S)-2-[(N-benzyl-N-((2S)-2-hydroxy-3-phenoxypropyl]amino]-3-(4-nitrophenyl)-1-propanol(1.12 g) in ethanol (11 ml)—water (2.2 ml) were added powdered iron (573mg) and ammonium chloride (55 mg). The mixture was gently heated toreflux for 1 hour and allowed to cool to room temperature. After theinsoluble material was filtered off, the filtrate was concentrated andpartitioned between chloroform and water. The organic layer wasseparated, washed successively with water and brine, dried overmagnesium sulfate, and filtered. The filtrate was concentrated and theresidue was purified by column chromatography (silica gel, hexane/ethylacetate) to give(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol(990 mg) as a pale yellow oil.

[0151] NMR (CDCl₃, δ): 2.44 (1H, dd, J=14 and 9 Hz), 2.70-3.20 (4H, m),3.42-4.02 (7H, m), 6.61 (2H, d, J=8 Hz), 6.82 (2H, d, J=9 Hz), 6.86-7.02(3H, m), 7.13-7.40 (7H, m)

[0152] MS m/z: 407 (M⁺+1)

[0153] Preparation 10

[0154] To a mixture ofN-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-benzamide(102 mg) and triethylamine (0.1 ml) in dichloromethane (1 ml) was addedacetic anhydride (50 μl), and the mixture was stirred at roomtemperature for 5 hours. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with brine,dried over magnesium sulfate, and filtered. The filtrate wasconcentrated to giveN-[4-[(2S)-3-acetoxy-2-[N-[(2S)-2-acetoxy-3-phenoxypropyl]-N-benzylamino]propyl]phenyl]-benzamide(124 mg) as a white amorphous powder.

[0155] NMR (CDCl₃, δ): 1.91 (3H, s), 2.04 (3H, s), 2.50-3.40 (5H, m),3.68-4.24 (6H, m), 4.98-5.20 (1H, m), 6.74-7.02 (3H, m), 7.13 (2H, d,J=9 Hz), 7.16-7.35 (7H, m), 7.42-7.60 (5H, m), 7.77 (1H, br s),7.80-7.92 (2H, m) MS m/z: 595 (M⁺+1)

[0156] Preparation 11

[0157] To an ice-cooled solution of tert-butyl(S)-4-(4-aminobenzenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (500mg) and pyridine (0.16 ml) in dichloromethane (60 ml) was added dropwisebenzoyl chloride (0.21 ml). The mixture was stirred at the sametemperature for 1 hour and partitioned between chloroform and saturatedsodium bicarbonate solution. The organic layer was separated, washedwith brine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated and the residue was purified by column chromatography(silica gel, hexane/ethyl acetate) to give tert-butyl(S)-4-[4-(benzoylamino)benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(690 mg) as colorless oil.

[0158] NMR (CDCl₃, δ): 2.80-3.00 (2H, m), 3.40-3.80 (3H, m), 7.00-7.50(9H, m)

[0159] MS m/z: 286 (M⁺+1)

[0160] Preparation 12

[0161] To a solution of tert-butyl(S)-4-[4-(benzoylamino)benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(690 mg) in methanol (20 ml) was added 4N hydrogen chloride in ethylacetate (5 ml) at room temperature, and the solution was stirred at thesame temperature for 4 hours. The mixture was evaporated in vacuo, andthe residue was partitioned between chloroform and saturated sodiumbicarbonate solution. The organic layer was separated, washed withbrine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated to give (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]benzamide(250 mg) as a colorless solid.

[0162] NMR (MeOD-d₄, δ): 2.95 (2H, d, J=7 Hz), 3.40-3.80 (3H, m), 7.30(2H, d, J=8 Hz), 7.40-8.00 (7H, m)

[0163] MS m/z: 271 (M⁺+1)

[0164] Preparation 13

[0165] To an ice-cooled solution of tert-butyl(S)-4-(4-aminobenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.0 g)in dichloromethane (10 ml) was added dropwise phenyl isocyanate (0.39ml). The mixture was stirred at the same temperature for 1 hour andpartitioned between chloroform and saturated sodium bicarbonatesolution. The organic layer was separated, washed with brine, dried overmagnesium sulfate, and filtered. The filtrate was concentrated and theresidue was purified by column chromatography (silica gel, hexane/ethylacetate) to give tert-butyl(S)-4-[4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.48 g) as colorless oil.

[0166] NMR (CDCl₃, δ): 1.50-1.70 (15H, m), 2.60 (1H, dd, J=10, 13 Hz),3.00-3.20 (1H, m), 3.70-3.80 (2H, m), 4.05-4.10 (1H, m), 6.88-7.40 (9H,m)

[0167] Preparation 14

[0168] To a solution of tert-butyl(S)-4-(4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate(1.48 g) in methanol (20 ml) was added 4N hydrogen chloride in ethylacetate (5 ml) at room temperature, and the solution was stirred at thesame temperature for 4 hours. The mixture was evaporated in vacuo, andthe residue was triturated with diisopropyl ether to give(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N′-phenylurea hydrochloride(660 mg) as a colorless solide.

[0169] NMR (MeOD-d₄, δ): 2.80-3.00 (2H, m), 3.40-3.80 (3H, m), 7.00-7.50(9H, m)

[0170] MS m/z: 286 (M⁺+1)

[0171] Preparation 15

[0172] To a solution of(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl)benzamide (207 mg) andbenzaldehyde (106 mg) in 1,4-dioxane (5 ml) was refluxed for 3 hours,and the mixture was evaporated in vacuo. To the residue in methanol (5ml) was added sodium borohydride (15 mg) on ice-cooling, and stirred atthe same temperature for 1 hour. The resulting mixture was poured intosaturated aqueous sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, and evaporated in vacuo. The residue was chromatographed(hexane-ethyl acetate) over silica gel to afford(S)-N-[4-[2-(benzylamino)-3-hydroxypropyl]phenyl]benzamide (250 mg) ascolorless oil.

[0173] NMR (CDCl₃, δ): 2.70-2.83 (2H, m), 2.88-2.98 (1H, m), 3.35 (1H,dd, J=5, 11Hz), 3.68 (1H, dd, J=4, 11Hz), 3.79 (2H, s), 7.10-7.90 (14H,m)

[0174] MS m/z: 361 (M⁺+1)

[0175] Preparation 16

[0176] To an ice-cooled solution of(2S)-1,2-epoxy-3-(3-formyl-4-benzyloxyphenoxy)propane (2.6 g) inmethanol (30 ml) was added sodium borohydride (381 mg). The mixture wasstirred at the same temperature for 1 hour and partitioned betweenchloroform and saturated sodium bicarbonate solution. The organic layerwas separated, washed with brine, dried over magnesium sulfate, andfiltered. The filtrate was concentrated to give(2S)-1,2-epoxy-3-(3-hydroxymethyl-4-benzyloxyphenoxy)propane (2.57 g) asa yellow oil.

[0177] NMR (CDCl₃, δ): 2.74 (1H, q, J=3 Hz), 2.89 (1H, t, J=5 Hz), 3.33(1H, m), 3.92 (2H, dd, J=5, 11Hz), 4.20 (1H, dd, J=3, 11Hz), 4.70 (2H,d, J=6 Hz), 5.1

[0178] (2H, s), 6.70-7.00 (3H, m), 7.32-7.45 (5H, m) MS m/z: 309 (M⁺+Na)

[0179] Preparation 17

[0180] To a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropyl)carbamate(200 mg) in 1,2-dichloroethane (2.0 ml) was addedN,O-bis(trimethylsilyl)acetamide (119 μl) at room temperature and thesolution was stirred for 30 minutes. To the solution was addedsuccessively ethyl 2-isocyanatobenzoate (110 mg) andN,N-diisopropylethylamine (8.36 μl) and the mixture was stirred for 2hours. The reaction mixture was diluted with ethyl acetate (20 ml) andwashed with water (20 ml×1) and brine (20 ml×1) successively, dried overmagnesium sulfate, and evaporated to give a pale yellow foam. The crudeproduct was purified by a recycling preparative high pressure liquidchromatography equipped with a gel permeation chromatography column(eluent: chloroform) and silica gel chromatography (eluent: hexane/ethylacetate=2/1) to give ethyl2-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl)amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate(217 mg) as a white foam.

[0181] MS (ESI) m/z: 702 (M+Na⁺)

[0182] Preparation 18

[0183] The following compounds were obtained according to a similarmanner to that of Preparation 17.

[0184] (1) Ethyl3-[[[[4-[(2S)-2-[(N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl)amino]-3-[(trimethylsilyl)-oxy]propyl]phenyl]amino]carbonyl]amino]benzoateMS (ESI) m/z: 702 (M+Na⁺)

[0185] (2) Ethyl4-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl)amino]-3-[(trimethylsilyl)-oxy]propyl]phenyl]amino]carbonyl]amino]benzoateMS (ESI) m/z: 702 (M+Na⁺)

[0186] Preparation 19

[0187] To a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropyl)carbamate(100 mg) in 1,2-dichloroethane (1.0 ml) was addedN,O-bis(trimethylsilyl)acetamide (59.3 μl) at room temperature and thesolution was stirred for 30 minutes. To the solution was addedsuccessively 2-nitrophenyl isocyanate (47.3 mg) and 1.0 M solution ofN,N-diisopropylethylamine in 1,2-dichloroethane (24 μl) and the mixturewas stirred for 90 minutes. To the mixture was added an additionalportion of N,O-bis(trimethylsilyl)acetamide (59.3 μl ) and the whole wasstirred overnight. The reaction mixture was diluted with ethyl acetate(20 ml) and washed with water (20 ml×1) and brine (20 ml×1)successively, dried over magnesium sulfate, and evaporated to give ayellow foam. The crude product was purified by a recycling preparativehigh pressure liquid chromatography equipped with a gel permeationchromatography column (eluent: chloroform) and silica gel chromatography(eluent: hexane/ethyl acetate 4/1) to give tert-butylN-[(1S)-1-[4-[[[(2-nitrophenyl)-amino]carbonyl]amino]benzyl]-2-[(trimethylsilyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamate(100 mg) as a yellow foam.

[0188] MS m/z: 747 (M+Na⁺)

[0189] Preparation 20

[0190] The following compounds were obtained according to a similarmanner to that of Preparation 19.

[0191] (1) tert-ButylN-[(1S)-1-[4-[[[(3-nitrophenyl)amino]-carbonyl]amino]benzyl]-2-[(trimethylsilyl)oxy]ethyl)-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamateMS m/z: 747 (MH⁺)

[0192] (2) tert-ButylN-[(1S)-1-[4-[[[(4-nitrophenyl)amino]-carbonyl]amino]benzyl]-2-[(trimethylsilyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamateMS m/z: 747 (MH⁺)

[0193] Preparation 21

[0194] To a suspension of(25)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (6.0 g) in ethanol (60ml) was added (2R)-2-(3-chlorophenyl)oxirane (4.86 g) and the mixturewas refluxed for 23 hours. After cooling to room temperature, thesolvent was removed by evaporation and the residue was chromatographedon silica gel (eluent: hexane/ethyl acetate=2/1) to give the(2S)-2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-nitrophenyl)-1-propanol(5.46 g) as a yellow crystalline solid.

[0195] MS m/z: 440 (MH⁺)

[0196] Preparation 22

[0197] To a solution of(2S)-2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-nitrophenyl)-1-propanol(5.33 g) in a mixed solvent of methanol (50 ml) and chlorobenzene (50ml) was added 10% palladium on activated carbon (50% wet, 1.00 g) andthe mixture was hydrogenated at 1 atm for 2 hours. The catalyst wasfiltered off and washed with methanol. The filtrate was concentrated invacuo to give(2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1-propanoldihydrochloride (4.95 g) as a pale yellow solid.

[0198] MS m/z: 321 (MH⁺)

[0199] Preparation 23

[0200] To a suspension of(2S)-3-(4-aminophenyl)-2-[((2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1-propanoldihydrochloride (3.68 g) in a mixed solvent of chloroform and methanol(9:1, 75 ml) was added a saturated aqueous sodium bicarbonate solution(75 ml) and the whole was stirred vigorously. The organic layer wasseparated and the aqueous layer was extracted with a mixed solvent ofchloroform and methanol (9:1, 25 ml×5). The organic layers werecombined, dried over magnesium sulfate, filtered, and evaporated to give(2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1-propanol(2.78 g) as a pale orange crystalline solid.

[0201] Preparation 24

[0202] To a solution of(2S)-3-(4-aminophenyl)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1-propanol(2.78 g) in tetrahydrofuran (28.0 ml) was added di-tert-butyldicarbonate (1.99 ml) and the solution was stirred at room temperaturefor 20 hours. The solvent was removed by evaporation and the residue waschromatographed on silica gel (eluent: hexane/ethyl acetate=1/1) to givetert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(1.57 g) as a pale yellow solid.

[0203] MS m/z: 443 (M+Na⁺)

[0204] Preparation 25

[0205] A solution of (2S)-2-[(4-(benzyloxy)phenoxy)methyl]-oxirane (1.19g) and (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (1.33 g) inethanol (13 ml) was refluxed for 20 hours. After cooling to roomtemperature, the solvent was removed by evaporation and the residue waschromatographed on silica gel (eluent: chloroform/methanol=98/2) to give(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-(4-nitrophenyl)-1-propanol(2.04 g) as a yellow gum.

[0206] MS m/z: 543 (MH⁺)

[0207] Preparation 26

[0208] A solution of(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-(4-nitrophenyl)-1-propanol(2.00 g) in a mixed solvent of ethanol (7.5 ml) and 1,4-dioxane (7.5 ml)was added dropwise to a stirred suspension of iron powder (2.00 g) andammonium chloride (0.24 g) in a mixed solvent of ethanol (5 ml) andwater (5 ml) at 85° C. over 10 minutes and the resulting mixture wasstirred at the same temperature for 30 minutes. The insoluble solid wasfiltered off and washed with dioxane, and the filtrate was concentratedin vacuo. The residue was partitioned between saturated aqueous sodiumhydrogencarbonate solution and ethyl acetate. The organic layer wasseparated, washed with brine, dried over magnesium sulfate, andevaporated to give(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]-amino]-1-propanol(1.90 g) as a pale yellow oil.

[0209] MS m/z: 513 (MH⁺)

[0210] Preparation 27

[0211] To a 0.024 M solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamatein 1,2-dichloromethane (15 ml) was addedN,O-bis(trimethylsilyl)acetamide (270 μl) and stirred overnight atambient temperature. Evaporation of the solvent gave a residue, whichwas purified by column chromatography on silica gel (eluent: 0-33% ethylacetate in hexane) to give tert-butylN-[(1S)-1-(4-aminobenzyl)-2-[(trimethylsilyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propylcarbamate(190 mg) as a yellow oil.

[0212] NMR (DMSO-d₆, δ): 0.02 (9H, s), 0.09 (9H, s), 1.42 (9H, s),2.55-2.70 (2H, m), 3.20-4.35 (8H, m), 4.87 (2H, s), 6.49 (2H, d, J=8.4Hz), 6.75-7.00 (5H, m), 7.20-7.35 (2H, m)

[0213] (+)-APCI MS m/z: 461 (M-CO₂-tert-butyl+H)⁺

EXAMPLE 1

[0214] To an ice-cooled solution of(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol(83 mg) in dichloromethane (0.8 ml) was added dropwise ethyl isocyanate(0.016 ml). The mixture was stirred at the same temperature for 1.5hours and partitioned between chloroform and saturated sodiumbicarbonate solution. The organic layer was separated, washed withbrine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated and the residue was purified by column chromatography(silica gel, chloroform/methanol) to giveN-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-ethylurea(84 mg) as a white amorphous powder.

[0215] NMR (CDCl₃, δ): 1.12 (3H, t, J=7 Hz), 2.51 (1H, dd, J=14 and 9Hz), 2.63-3.37 (6H, m), 3.37-4.02 (7H, m), 4.85 (1H, t, J=6 Hz), 6.46(1H, s), 6.81 (2H, d, J=9 Hz), 6.86-7.40 (12H, m)

[0216] MS m/z: 478 (M⁺+1)

EXAMPLE 2

[0217] A solution ofN-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-ethylurea(73 mg) in methanol (1.5 ml) was hydrogenated (1 atm) over 10% palladiumon carbon (11 mg) at room temperature for 12 hours. After the catalystwas filtered off, the filtrate was concentrated and the residue waspurified by column chromatography (silica gel, chloroform/methanol)followed by recrystallization from ehtanol/hexane to giveN-ethyl-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-propyl]phenyl]urea(38 mg) as a white powder.

[0218] mp: 129-130° C.

[0219] IR (KBr): 1678, 1637, 1597, 1558 cm⁻¹

[0220] NMR (CD₃OD, δ): 1.14 (3H, t, J=7 Hz), 2.62-3.16 (5H, m), 3.21(2H, q, J=7 Hz), 3.45 (1H, dd, J=1 and 6 Hz), 3.63 (1H, dd, J=11 and 4Hz), 3.90-4.20 (3H, m), 6.84-7.36 (9H, m)

[0221] MS m/z: 388 (M⁺+1)

EXAMPLE 3

[0222] To an ice-cooled solution of(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol(76 mg) in dichloromethane (0.8 ml) was added dropwise phenyl isocyanate(0.022 ml), and the mixture was stirred at the same temperature for 40minutes. One drop of 28% ammonia solution was added to the mixture, themixture was concentrated, and the residue was purified by columnchromatography (silica gel, chloroform/methanol) to giveN-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-3-hydroxypropyl]phenyl]-N′-phenylurea(89 mg) as a white amorphous powder.

[0223] NMR (CDCl₃, δ): 2.48 (1H, dd, J=13 and 8 Hz), 2.63-3.22 (4H, m),3.38-4.02 (7H, m), 6.66-7.43 (21H, m)

[0224] MS m/z: 526 (M⁺+1)

EXAMPLE 4

[0225] The following compounds were obtained according to a similarmanner to that of Example 2.

[0226] (1)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]phenyl]-N′-phenylurea

[0227] IR (KBr): 3440-2921, 1641, 1596, 1560, 1498, 1315, 1238 cm⁻¹

[0228] NMR (DMSO-d₆, δ): 2.50-2.64 (5H, m), 3.10-3.20 (2H, m), 3.80-4.00(3H, m), 4.50-4.60 (1H, m), 4.93 (1H, d, J=4.2 Hz), 6.85-7.00 (4H, m),7.05-7.15 (2H, m), 7.25-7.50 (8H, m), 8.57 (1H, s), 8.63 (1H, s) MS m/z:436 (M⁺+1)

[0229] (2)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]phenyl)benzamidemp: 124-125° C.

[0230] IR (KBr): 1655, 1599, 1529 cm⁻¹

[0231] NMR (CD₃OD, δ): 2.58-3.05 (5H, m), 3.43 (1H, dd, J=11 and 6 Hz),3.60 (1H, dd, J=11 and 4 Hz), 3.83-4.15 (3H, m), 6.80-7.00 (3H, m),7.12-7.35 (4H, m), 7.40-7.70 (5H, m), 7.83-8.01 (2H, m)

[0232] MS m/z: 421 (M⁺+1)

[0233] (3)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-4-methoxybenzamide

[0234] NMR (CDCl₃-CD₃OD(1:1), δ): 2.60-3.12 (5H, m), 3.45 (1H, dd, J=11and 6 Hz), 3.64 (1H, dd, J=11 and 4 Hz), 3.89 (3H, s), 3.90-4.20 (3H,m), 6.80-7.12 (5H, m), 7.12-7.40 (4H, m), 7.60 (2H, d, J=8 Hz), 7.91(2H, d, J=9 Hz)

[0235] MS m/z: 451 (M⁺+1)

[0236] (4)4-Chloro-N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]benzamide

[0237] NMR (CDCl₃-CD₃OD(1:1), δ): 2.66-3.15 (5H, m), 3.47 (1H, dd, J=11and 6 Hz), 3.66 (1H, dd, J=11 and 4 Hz), 3.86-4.20 (3H, m), 6.82-7.06(3H, m), 7.13-7.38 (4H, m), 7.48 (2H, d, J=8 Hz), 7.62 (2H, d, J=8 Hz),7.90 (2H, d, J=9 Hz)

[0238] MS m/z: 455 (M⁺+1)

[0239] (5)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]phenyl]-3-methoxybenzamide

[0240] NMR (CDCl₃-CD₃OD(1:1), δ): 2.60-3.10 (5H, m), 3.44 (1H, dd, J=11and 6 Hz), 3.63 (1H, dd, J=11 and 4 Hz), 3.88 (3H, s), 3.88-4.15 (3H,m), 6.80=7.74 (13H, m)

[0241] MS m/z: 451 (M⁺+1)

[0242] (6)3-Chloro-N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]benzamide

[0243] NMR (CDCl₃-CD₃OD(1:1), δ): 2.58-3.11 (5H, m), 3.44 (1H, dd, J=11and 6 Hz), 3.63 (1H, dd, J=11 and 4 Hz), 3.85-4.18 (3H, m), 6.80-8.02(13H, m)

[0244] MS m/z: 455 (M⁺+1)

[0245] (7)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1-naphthamide

[0246] NMR (CDCl₃—CD₃OD(1:1), δ): 2.60-3.10 (5H, m), 3.45 (1H, dd, J=11and 6 Hz), 3.62 (1H, dd, J=11 and 4 Hz), 3.82-4.22 (3H, m), 6.82-8.33(16H, m)

[0247] MS m/z: 471 (M⁺+1)

[0248] (8)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-2-naphthamide

[0249] NMR (CDCl₃—CD₃OD(1:1), δ): 2.72-3.23 (5H, m), 3.58 (1H, dd, J=11and 6 Hz), 3.76 (1H, dd, J=11 and 4 Hz), 3.95-4.30 (3H, m), 6.90-8.25(15H, m), 8.59 (1H, s)

[0250] MS m/z: 471 (M⁺+1)

[0251] (9)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1H-pyrrole-2-carboxamide

[0252] NMR (CDCl₃-CD₃OD(1:1), δ): 2.76-3.30 (5H, m), 3.63 (1H, dd, J=11and 6 Hz), 3.82 (1H, dd, J=11 and 4 Hz), 4.03-4.37 (3H, m), 6.39-6.49(1H, m), 6.98-7.29 (5H, m), 7.29-7.57 (4H, m), 7.76 (2H, d, J=8 Hz)

[0253] MS m/z: 410 (M⁺+1)

[0254] (10)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]nicotinamide

[0255] NMR (DMSO-d₆, δ): 2.53-3.05 (5H, m), 3.29 (1H, dd, J=11 and 6Hz), 3.44 (1H, dd, J=11 and 4 Hz), 3.76-4.10 (3H, m), 6.80-7.04 (3H, m),7.13-7.38 (4H, m), 7.57 (1H, dd, J=8 and 5 Hz), 7.70 (2H, d, J=8 Hz),8.29 (1H, ddd, J=8, 2 and 2 Hz), 8.76 (1H, dd, J=5 and 2 Hz), 9.11 (12H,d, J=2 Hz), 10.45 (1H, br s)

[0256] MS m/z: 422 (M⁺+1).

[0257] (11)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N-methylbenzamide

[0258] mp: 115-116° C.

[0259] IR (KBr): 1637, 1601 cm⁻¹

[0260] NMR (CDCl₃, δ): 2.53-3.00 (5H, m), 3.32 (1H, dd, J=11 and 5 Hz),3.47 (3H, s), 3.58 (1H, dd, J=11 and 4 Hz), 3.84-4.10 (3H, m), 6.80-7.38(14H, m)

[0261] MS m/z: 435 (M⁺+1)

[0262] (12)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-[4-hydroxy-3-(hydroxymethyl)phenoxy]propyl]amino]propyl]phenyl]-benzamide

[0263] IR (KBr): 3500-3000, 1641, 1600, 1446, 1029 cm⁻¹

[0264] NMR (MeOD-d₄, δ): 2.90-3.10 (3H, m), 3.30-3.60 (4H, m),3.80-4.00.(2H, m), 4.10-4.30 (1H, m), 4.71 (2H, s), 6.67 (2H, s), 6.93(1H, s), 7.10-7.90 (9H, m)

[0265] MS m/z: 467 (M⁺+1)

EXAMPLE 5

[0266] To an ice-cooled mixture of(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol(63 mg) and pyridine (25 μl) in dichloromethane (0.6 ml) was addeddropwise benzoyl chloride (22 μl), and the mixture was stirred at roomtemperature for more than 2 hours. The mixture was partitioned betweenchloroform-methanol and water. The organic layer was separated, washedwith brine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated and the residue was purified by column chromatography(silica gel, chloroform/methanol) to giveN-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]benzamide(80 mg) as a white amorphous powder.

[0267] NMR (CDCl₃, δ): 2.56 (1H, dd, J=14 and 9 Hz), 2.72-3.28 (4H, m),3.44-4.04 (7H, m), 6.83 (2H, d, J=9 Hz), 6.86-7.03 (1H, m), 7.14 (2H, d,J=8 Hz), 7.20-7.40 (7H, m), 7.40-7.63 (5H, m), 7.78-7.96 (2H, m), 7.80(1H, br s)

[0268] MS m/z: 511 (M⁺+1)

EXAMPLE 6

[0269] To a mixture of(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol(77 mg) and benzoic acid (28 mg) in N,N-dimethylformamide (0.8 ml) wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57mg), and the mixture was stirred at room temperature for 20 hours. Themixture was partitioned between hexane-ethyl acetate and water. Theorganic layer was separated, washed successively with water and brine,dried over magnesium sulfate, and filtered. The filtrate wasconcentrated to giveN-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino)-3-hydroxypropyl]phenyl]-benzamide(95 mg) as a white amorphous powder.

[0270] NMR (CDCl₃, δ): 2.56 (1H, dd, J=14 and 9 Hz), 2.71-3.28 (4H, m),3.42-4.03 (7H, m), 6.82 (2H, d, J=9 Hz), 6.88-7.02 (1H, m), 7.14 (2H, d,J=8 Hz), 7.18-7.38 (7H, m), 7.38-7.65 (5H, m), 7.77-7.97 (2H, m), 7.80(1H, br s)

[0271] MS m/z: 511 (M⁺+1)

EXAMPLE 7

[0272] The following compounds were obtained according to a similarmanner to that of Example 6.

[0273] (1)N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-4-methoxybenzamide

[0274] NMR (CDCl₃, δ): 2.55 (1H, dd, J=13 and 9 Hz), 2.71-3.26 (4H, m),3.45-4.02 (7H, m), 3.86 (3H, s), 6.73-7.38 (14H, m), 7.53 (2H, d, J=8Hz), 7.77 (1H, br s), 7.84 (2H, d, J=9 Hz)

[0275] MS m/z: 541 (M⁺+1)

[0276] (2)N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-4-chlorobenzamide

[0277] NMR (CDCl₃, δ): 2.56 (1H, dd, J=13 and 9 Hz), 2.70-3.28 (4H, m),3.43-4.05 (7H, m), 6.73-7.03 (3H, m), 7.13 (2H, d, J=9 Hz), 7.17-7.36(7H, m), 7.46 (2H, d, J=9 Hz), 7.52 (2H, d, J=8 Hz), 7.77 (1H, br s),7.81 (2H, d, J=9 Hz)

[0278] MS m/z: 545 (M⁺+1)

[0279] (3)N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-3-methoxybenzamide

[0280] NMR (CDCl₃, δ): 2.56 (1H, dd, J=14 and 9 Hz), 2.70-3.30 (4H, m),3.42-4.03 (7H, m), 3.87 (3H, s), 6.73-7.62 (18H, m), 7.80 (1H, br s)

[0281] MS m/z: 541 (M⁺+1)

[0282] (4)N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-3-chlorobenzamide

[0283] NMR (CDCl₃, δ): 2.56 (1H, dd, J=14 and 9 Hz), 2.72-3.30 (4H, m),3.42-4.05 (7H, m), 6.74-7.93 (19H, m)

[0284] MS m/z: 545 (M⁺+1)

[0285] (5)N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropylphenyl]-1-naphthamide

[0286] NMR (CDCl₃, δ): 2.58 (1H, dd, J=14 and 9 Hz), 2.72-3.28 (4H, m),3.28-4.03 (7H, m), 6.72-8.04 (21H, m), 8.26-8.45 (1H, m)

[0287] MS m/z: 561 (M⁺+1)

[0288] (6)N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-2-naphthamide

[0289] NMR (CDCl₃, δ): 2.57 (1H, dd, J=14 and 9 Hz), 2.72-3.30 (4H, m),3.42-4.04 (7H, m), 6.72-8.07 (21H, m), 8.38 (1H, s)

[0290] MS m/z: 561 (M⁺+1)

EXAMPLE 8

[0291] To a mixture of(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol(79 mg) and pyrrole-2-carboxylic acid (26 mg) in dichloromethane (0.8ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (59 mg), and the mixture was stirred at room temperaturefor 47 hours. The mixture was partitioned between ethyl acetate andwater. The organic layer was separated, washed with brine, dried overmagnesium sulfate, and filtered. The filtrate was concentrated, and theresidue was purified by column chromatography (silica gel, hexane/ethylacetate) to giveN-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]-phenyl]-1H-pyrrole-2-carboxamide(48 mg) as a white amorphous powder.

[0292] NMR (CDCl₃, δ): 2.53 (1H, dd, J=14 and 9 Hz), 2.68-3.28 (4H, m),3.42-4.04 (7H, m), 6.23-6.34 (1H, m), 6.65-6.75 (1H, m), 6.75-7.05 (4H,m), 7.10 (2H, d, J=8 Hz), 7.17-7.41 (7H, m), 7.49 (2H, d, J=8 Hz)₁ 7.58(1H, br s), 9.56 (1H, br s)

[0293] MS m/z: 500 (M⁺+1)

EXAMPLE 9

[0294] The following compound was obtained according to a similar mannerto that of Example 5.

[0295]N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]nicotinamide

[0296] NMR (CDCl₃, δ): 2.56 (1H, dd, J=14 and 9 Hz), 2.70-3.30 (4H, m),3.42-4.04 (7H, m), 6.72-7.05 (3H, m), 7.14 (2H, d, J=8 Hz), 7.18-7.38(7H, m), 7.44 (1H, dd, J=8 and 5 Hz), 7.54 (2H, d, J=8 Hz), 7.98 (1H, brs), 8.21 (1H, ddd, J=8, 2 and 2 Hz), 8.76 (1H, dd, J=5 and 2 Hz), 9.08(1H, d, J=2 Hz)

[0297] MS m/z: 512(M⁺+1)

EXAMPLE 10

[0298] To an ice-cooled solution ofN-[4-[(2S)-3-acetoxy-2-[N-[(2S)-2-acetoxy-3-phenoxypropyl]-N-benzylamino]propyl]-phenyl]benzamide(107 mg) in tetrahydrofuran (1.1 ml) was added sodium hydride (60% inoil, 17 mg), and the mixture was stirred at the same temperature for 30minutes. To the mixture was added iodomethane (25 μl), and the mixturewas stirred at room temperature for 1.5 hours before being partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith brine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated and the residue was dissolved in methanol (1.1ml)-1,4-dioxane (1.1 ml), then treated with 1N sodium hydroxide (0.5 ml)at room temperature for 1.5 hours. The mixture was concentrated andpartitioned between ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over magnesium sulfate, andfiltered. The filtrate was concentrated and the residue was purified bycolumn chromatography (silica gel, hexane/ethyl acetate) to giveN-[4-[(2S)-2-(N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-3-hydroxypropyl]phenyl]-N-methylbenzamide(55 mg) as a white amorphous powder.

[0299] NMR (CDCl₃, δ): 2.49 (1H, d, J=14 and 9 Hz), 2.65-3.22 (4H, m),3.34-3.72 (3H, m), 3.47 (3H, s), 3.72-4.04 (4H, m), 6.74-7.40 (19H, m)

[0300] MS m/z: 525 (M⁺+1)

EXAMPLE 11

[0301] To a 0.5 M solution of tert-butylN-((1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-((2S)-2-hydroxy-3-phenoxypropyl)carbamatein dichloroethane (40 μl) were added successively 2.0 M solution ofN,O-bis(trimethylsilyl)-acetamide in 1-methyl-2-pyrrolidinone (10 μl),1.0 M solution of ethyl isocyanate in 1-methyl-2-pyrrolidinone (24 μl),and 0.1 M solution of N-ethyldiisopropylamine in1-methyl-2-pyrrolidinone (20 μl) at room temperature. After shaking atroom temperature for 30 minutes, the solution was treated with 500 μl oftrifluoroacetic acid/water (95/5) at 50° C. for 30 minutes. The mixturewas evaporated and the residue was purified by reverse phase HPLC(0-100% acetonitrile in water (containing 0.1% trifluoroacetic acid)) togiveN-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-propylureatrifluoroacetate (5.51 mg) as a pale yellow oil.

[0302] MS m/z: 402(M⁺+1)

EXAMPLE 12

[0303] The following compounds were obtained according to a similarmanner to that of Example 11.

[0304] (1)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-isopropylureatrifluoroacetate

[0305] MS m/z: 402 (M⁺+1)

[0306] (2)N-(2-Chlorophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0307] MS m/z: 470 (M⁺+1)

[0308] (3)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-(3-nitrophenyl)ureatrifluoroacetate

[0309] MS m/z: 450 (M⁺+1)

[0310] (4)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-(3-methoxyphenyl)ureatrifluoroacetate

[0311] MS m/z: 466 (M⁺+1)

[0312] (5)N-Benzoyl-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0313] MS m/z: 464 (M⁺+1)

[0314] (6)N-Cyclohexyl-N′-(4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0315] MS m/z: 442 (M⁺+1)

[0316] (7)N-(3-Fluorophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0317] MS m/z: 454 (M⁺+1)

[0318] (8)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-4-methoxyphenyl)ureatrifluoroacetate

[0319] MS m/z: 466 (M⁺+1)

[0320] (9)N-(2-Chloroethyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]phenyl]ureatrifluoroacetate

[0321] MS m/z: 422 (M⁺+1)

[0322] (10)N-(3-Bromophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0323] MS m/z: 515 (M⁺+1)

[0324] (11)N-(4-Bromophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0325] MS m/z: 515 (M⁺+1)

[0326] (12)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-(3-methylphenyl)ureatrifluoroacetate

[0327] MS m/z: 450 (M⁺+1)

[0328] (13)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-(2-methylphenyl)ureatrifluoroacetate

[0329] MS m/z: 450 (M⁺+1)

[0330] (14)N-(3-Acetylphenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0331] MS m/z: 478 (M⁺+1)

[0332] (15)N-(3-Cyanophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0333] MS m/z: 461 (M⁺+1)

[0334] (16) Ethyl[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]anilino]carbonyl]amino]-acetatetrifluoroacetate

[0335] MS m/z: 446 (M⁺+1)

[0336] (17)N-(2,3-Dichlorophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0337] MS m/z: 505 (M⁺+1)

[0338] (18)N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-propyl]phenyl]ureatrifluoroacetate

[0339] MS m/z: 538 (M⁺+1)

[0340] (19)N-(2-Fluorophenyl)-N′-[4-[(2S)-3-hydroxy-2-[((2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]phenyl]ureatrifluoroacetate

[0341] MS m/z: 454 (M⁺+1)

[0342] (20)N-(4-Fluorophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0343] MS m/z: 454 (M⁺+1)

[0344] (21)N-(3-Chlorophenyl)-N′-[4-((2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0345] MS m/z: 470 (M⁺+1)

[0346] (22)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl)amino]propyl]phenyl]-N′-(2-nitrophenyl)ureatrifluoroacetate

[0347] MS m/z: 481 (M⁺+1)

[0348] (23)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-(4-nitrophenyl)ureatrifluoroacetate

[0349] MS m/z: 481 (M⁺+1)

[0350] (24)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-[2-(trifluoromethyl)phenyl]ureatrifluoroacetate

[0351] MS m/z: 504 (M⁺+1)

[0352] (25)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-[3-(trifluoromethyl)phenyl]ureatrifluoroacetate

[0353] MS m/z: 504 (M⁺+1)

[0354] (26)N-Benzyl-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]ureatrifluoroacetate

[0355] MS m/z: 450 (M⁺+1)

EXAMPLE 13

[0356] To an ice-cooled solution of(2S)-1-phenoxy-3-[N-[(2S)-2-(4-aminophenyl)-1-(hydroxymethyl)ethyl]-N-benzylamino]-2-propanol(95 mg) and pyridine (37 mg) in dichloromethane (1 ml) was addeddropwise acetic anhydride (26.2 mg). The mixture was stirred at the sametemperature for 1 hour and partitioned between chloroform and saturatedsodium bicarbonate solution. The organic layer was separated, washedwith brine, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated. A solution of the residue in methanol (1 ml) washydrogenated (1 atm) over 10% palladium on carbon (15 mg) at roomtemperature for 2 hours. After the catalyst was filtered off, thefiltrate was concentrated and the residue was purified by columnchromatography (silica gel, chloroform/methanol) to give(2S)-1-phenoxy-3-[[(2S)-2-(4-acetamidophenyl)-1-(hydroxymethyl)ethyl]amino]-2-propanol(50 mg) as a colorless form.

[0357] IR (KBr): 3300-3200, 1664, 1602, 1407, 1243 cm⁻¹

[0358] NMR (CDCl₃, δ): 2.11 (3H, s), 2.70-3.20 (5H, m), 3.40-3.70 (2H,m), 3.97 (2H, d, J=4.6 Hz), 4.10 (1H, m), 6.80-6.90 (3H, m), 7.10-7.30(4H, m), 7.48 (2H, d, J=8.5 Hz)

[0359] MS m/z: 359 (M⁺+1)

EXAMPLE 14

[0360] The following compound was obtained according to a similar mannerto that of Example 13.

[0361](2S)-1-Phenoxy-3-[[(2S)-2-(4-ureidophenyl)-1-(hydroxymethyl)ethyl]amino]-2-propanol

[0362] IR (KBr): 3500-3200, 1658, 1589, 1548, 1243 cm⁻¹

[0363] NMR (CDCl₃, δ): 2.65-3.00 (5H, m), 3.30-3.80 (2H, m), 3.90-4.05(3H, m), 6.90-7.40 (9H, m)

[0364] MS m/z: 391 (M⁺+1)

EXAMPLE 15

[0365] Under nitrogen, a solution of(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N′-phenylurea hydrochloride(150 mg), (R)-3-chlorostyrene oxide (56 mg) andN,N-diisopropylethylamine (0.17 ml) in ethanol (5 ml) was refluxed for28 hours. The mixture was evaporated in vacuo. The residue was purifiedby column chromatography on silica gel (chloroform:methanol=100:1) togiveN-[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea(45 mg) as a colorless form.

[0366] IR (KBr): 3500-3000, 1648, 1540, 1513, 1313, 1230 cm⁻¹

[0367] NMR (MeOD-d₄, δ): 2.60-2.90 (5H, m), 3.40-3.60 (2H, m), 4.60-4.70(1H, m), 6.90-7.40 (13H, m)

[0368] MS m/z: 440 (M⁺+1)

EXAMPLE 16

[0369] The following compounds were obtained according to a similarmanner to that of Example 15.

[0370] (1)N-[4-[(2S)-2-[[(2S)-3-(1H-Indol-4-yloxy)-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea

[0371] IR (KBr): 3400-3000, 1644, 1540, 1438, 1228, 1060 cm⁻¹

[0372] NMR (MeOD-d₄, δ): 2.60-3.10 (5H, m), 3.30-3.60 (2H, m), 4.00-4.10(3H, m), 6.40-6.60 (2H, m), 6.90-7.45 (12H, m)

[0373] MS m/z: 475 (M⁺+1)

[0374] (2)N-[4-[(2S)-2-[[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea

[0375] IR (KBr): 3300-3000, 1637, 1598, 1554, 1504, 1207 cm⁻¹

[0376] NMR (MeOD-d₄, δ): 2.60-3.10 (5H, m), 3.40-3.70 (2H, m), 4.05-4.40(3H, m), 6.90-7.50 (15H, m), 8.3 (1H, d, J=7 Hz)

[0377] MS m/z: 525 (M⁺+1)

[0378] (3)N-[4-[(2S)-2-[[(2S)-3-(4-Fluorophenoxy)-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea

[0379] IR (KBr): 3300-3000, 1637, 1598, 1554, 1504, 1207 cm⁻¹

[0380] NMR (MeOD-d₄, δ): 2.50-2.95 (5H, m), 3.30-3.65 (2H, m), 3.90-4.10(3H, m), 6.90-7.50 (9H, m)

[0381] MS m/z: 454 (M⁺+1)

[0382] (4)N-[4-[(2S)-2-[N-Benzyl-N-[(2S)-3-[4-(benzyloxy)-3-(hydroxymethyl)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]benzamide

[0383] NMR (CDCl₃, δ): 2.30-3.00 (6H, m), 3.05-3.20 (1H, m), 3.40-4.00(7H, m), 4.60 (2H, d, J=6.4 Hz), 5.00 (2H, s), 6.67 (1H, dd, J=3, 9 Hz),6.80-6.85 (2H, m), 7.10-7.60 (18H, m), 7.80-7.90 (3H, m)

[0384] MS m/z: 647 (M⁺+1)

EXAMPLE 17

[0385] To a solution of 10% hydrogen chloride in methanol was addedN-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino)propyl]phenyl]-N′-phenylurea(70 mg) and stirred for 15 minutes. The reaction mixture wasconcentrated and followed by recrystallization from ethanol to giveN-[4-[(2S)-3-hydroxy-2-([(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-phenylureahydrochloride (38 mg) as a white powder.

[0386] IR (KBr): 3330-2950, 1697, 1600, 1556, 1498, 1319, 1238 cm⁻¹

[0387] NMR (DMSO-d₆, δ): 2.70-3.35 (4H, m), 3.40-3.70 (3H, m) 4.00 (2H,d, J=5.0 Hz), 4.15-4.30 (1H, m), 5.41 (1H, s), 5.87 (1H, d, J=4.8 Hz),6.90-7.00 (4H, m), 7.15-7.50 (10H, m), 9.06 (1H, s), 9.07 (1H, s)

[0388] MS m/z: 436 (M⁺+1)

EXAMPLE 18

[0389] To a solution of ethyl2-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl)amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate(10.0 mg) in 1,2-dichloroethane (100 μl) was added trifluoroacetic acid(100 μl) and the solution was stirred at room temperature for 30minutes. The solvent was removed by evaporation to give ethyl2-[[[[4-[(2S)-3-hydroxy-2-([(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]-carbonyl]amino]benzoatetrifluoroacetate (10.3 mg) as a white foam.

[0390] MS m/z: 508 (MH⁺)

EXAMPLE 19

[0391] The following compounds were obtained according to a similarmanner to that of Example 18.

[0392] (1) Ethyl3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]benzoatetrifluoroacetate MS m/z: 508 (MH⁺)

[0393] (2) Ethyl4-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]benzoatetrifluoroacetate

[0394] MS m/z: 508 (MH⁺)

EXAMPLE 20

[0395] To a solution of tert-butylN-((1S)-1-[4-[[((2-nitrophenyl)amino]carbonyl]amino]benzyl]-2-(trimethylsilyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamate(95.0 mg) in methanol (2.9 ml) was added 10% palladium on activatedcarbon (50% wet, 95 mg) and the mixture was hydrogenated at 1 atm for 1hour. The catalyst was filtered off and the filtrate was concentrated invacuo to give tert-butylN-[(1S)-1-[4-[[[(2-aminophenyl)amino]carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate(75.3 mg) as a brown solid.

[0396] MS (ESI) m/z: 573 (M+Na⁺)

EXAMPLE 21

[0397] The following compounds were obtained according to a similarmanner to that of Example 20.

[0398] (1) tert-ButylN-[(1S)-1-[4-[[[(3-aminophenyl)amino]-carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

[0399] MS (ESI) m/z: 573 (M+Na⁺)

[0400] (2) tert-ButylN-[(1S)-1-[4-[[[(4-aminophenyl)amino]-carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

[0401] MS (ESI) m/z: 573 (M+Na⁺)

EXAMPLE 22

[0402] To a solution of tert-butylN-[(1S)-1-[4-[[[(2-aminophenyl)amino]carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate(20.0 mg) in 1,2-dichloroethane (200 μl) were added successively 1.0 Msolution of pyridine in 1,2-dichloroethane (54.5 μl) and 1.0 M solutionof methanesulfonyl chloride in 1,2-dichloroethane (43.6 μl) at roomtemperature. After stirring for 2 hours, the solvent was removed byevaporation and the residue was purified by a recycling preparative highpressure liquid chromatography equipped with a gel permeationchromatography column (eluent: chloroform) to give a light brown solid.The solid was dissolved in 1,2-dichloroethane (200 μl). To the solutionwas added trifluoroacetic acid (200 μl) and the mixture was stirred for30 minutes. The solvent was removed by evaporation to giveN-[2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]-carbonyl]amino]phenyl]methanesulfonamidetrifluoroacetate (20.3 mg) as a light brown solid.

[0403] MS m/z: 529 (MH⁺)

EXAMPLE 23

[0404] The following compounds were obtained according to a similarmanner to that of Example 22.

[0405] (1) MethylN-[2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]phenyl]carbamatetrifluoroacetate

[0406] MS m/z: 509 (MH⁺)

[0407] (2)N-[3-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]phenyl]methanesulfonamidetrifluoroacetate

[0408] MS m/z: 529 (MH⁺)

[0409] (3) MethylN-[3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]phenyl]carbamatetrifluroacetate

[0410] MS m/z: 509 (MH⁺)

[0411] (4)N-[4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino)propyl]phenyl]amino]carbonyl]-amino]phenyl]methanesulfonamidetrifluoroacetate

[0412] MS m/z: 529 (MH⁺)

[0413] (5) MethylN-[4-[[((4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]phenyl]carbamatetrifluoroacetate

[0414] MS m/z: 509 (MH⁺)

EXAMPLE 24

[0415] To a solution of ethyl3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate(204 mg) in 1,2-dichloroethane (2.0 ml) was added trifluroacetic acid(2.0 ml) and the solution was stirred at room temperature for 1 hour.The solvent was removed by evaporation and the residue was dissolved inethyl acetate (10 ml). The solution was washed with aqueous saturatedsodium bicarbonate solution (5 ml×1) and brine (10 ml×1) successively,dried over magnesium sulfate, and evaporated to give ethyl3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]amino]-benzoate(148 mg) as a white solid.

EXAMPLE 25

[0416] The following compound was obtained according to a similar mannerto that of Example 24.

[0417] Ethyl4-[[[[4-[(2S)-3-hydroxy-2-[((2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino)carbonyl]amino]-benzoate

EXAMPLE 26

[0418] To a solution of ethyl3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-amino]carbonyl]amino]benzoate(148 mg) in ethanol (2.0 ml) was added 1N sodium hydroxide solution (292μl) and the solution was refluxed for 4 hours. An additional portion of1N sodium hydroxide solution (58.3 μl) was added and the whole wasrefluxed for 3 hours. After cooling to room temperature, the solvent wasremoved by evaporation to give sodium3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]amino)-benzoate(158 mg) as a white solid.

[0419] MS m/z: 502 (MH⁺)

EXAMPLE 27

[0420] The following compound was obtained according to a similar mannerto that of Example 26.

[0421] Sodium4-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl)amino]carbonyl]amino]-benzoate

[0422] MS m/z: 502 (MH⁺)

EXAMPLE 28

[0423] To a solution of sodium3-[[[[4-[(2S)-3-hydroxy-2-[((2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-amino]carbonyl]amino]benzoate(50.0 mg) in a mixed solvent of tetrahydrofuran (1.0 ml) and water (1.0ml) was added 1N sodium hydroxide solution (99.7 μl). To the solutionwas added di-tert-butyl dicarbonate (27.5 μl) at room temperature andthe mixture was stirred for 2 hours. An additional portion ofdi-tert-butyl dicarbonate (27.5 μl) was added and the mixture wasstirred for 30 minutes. To the mixture was added pH 4.0 buffer solution(10 ml) and the resulting suspension was extracted with ethyl acetate(30 ml×1). The organic layer was separated and washed with brine (10ml×1), dried over magnesium sulfate, and evaporated to give3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-amino]carbonyl]amino]benzoicacid (47.3 mg) as a yellow solid.

EXAMPLE 29

[0424] The following compound was obtained according to a similar mannerto that of Example 28.

[0425]4-[[[[4-[(2S)-2-[N-(tert-Butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-amino]carbonyl]amino]benzoicacid

[0426] MS (negative) m/z: 578 (M−H⁺)

EXAMPLE 30

[0427] To a solution of3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]amino]benzoicacid (10.0 mg) in N,N-dimethylformamide (100 μl) were added successivelya 1.0 M solution of 1-hydroxybenzotriazole hydrate inN,N-dimethylformamide (20.7 μl) and a 1.0 M solution of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in 1,2-dichloroethane(20.7 μl) at room temperature. To the solution was added methylaminehydrochloride (1.4 mg) and the mixture was stirred for 4 hours. Thereaction mixture was diluted with ethyl acetate (10 ml) and washed withwater (10 ml×1) and brine (10 ml×1) successively, dried over magnesiumsulfate, and evaporated to give a pale yellow paste. The crude productwas purified by a recycling preparative high pressure liquidchromatography equipped with a gel permeation chromatography column(eluent:

[0428] chloroform) to give tert-butyl(1S)-2-hydroxy-1-[4-[[[[3-(methylcarbamoyl)phenyl]amino]carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate(7.2 mg) as a pale yellow solid.

EXAMPLE 31

[0429] The following compounds were obtained according to a similarmanner to that of Example 30.

[0430] (1) tert-ButylN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[[[3-(propylcarbamoyl)phenyl]amino]-carbonyl]amino]benzyl]ethyl]carbamate

[0431] (2) tert-ButylN-[(1S)-1-[4-[[[[3-(dimethylcarbamoyl)-phenyl]amino]carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

[0432] (3) tert-ButylN-[(1S)-2-hydroxy-1-[4-[[[[4-(methylcarbamoyl)phenyl]amino]carbonyl]amino]benzyl]-ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

[0433] (4) tert-ButylN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[[[4-(propylcarbamoyl)phenyl]amino]-carbonyl]amino]benzyl]ethyl]carbamate

[0434] (5) tert-ButylN-[(1S)-1-[4-[[[[4-(dimethylcarbamoyl)-phenyl]amino]carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

EXAMPLE 32

[0435] To a solution of tert-butylN-[(1S)-2-hydroxy-1-[4-[[[[3-(methylcarbamoyl)phenyl]amino)carbonyl]amino]benzyl]-ethyl]-N-[(2S)-2-hydroxy-3-phenoxypopyl]carbamate(7.2 mg) in a mixed solvent of 1,2-dichloroethane (100 μl) and methanol(25 μl) was added trifluoroacetic acid (100 μl) and the mixture wasstirred at room temperature for 3 hours. The solvent was removed byevaporation to give3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-propyl]phenyl]amino]carbonyl]amino]-N-methylbenzamidetrifluroacetate (7.2 mg) as a pale yellow foam.

[0436] MS m/z: 493 (MH⁺)

EXAMPLE 33

[0437] The following compounds were obtained according to a similarmanner to that of Example 32.

[0438] (1)3-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]-N-propylbenzamidetrifluroacetate

[0439] MS m/z: 521 (MH⁺)

[0440] (2)3-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]-N,N-dimethylbenzamidetrifluoroacetate

[0441] MS m/z: 507 (MH⁺)

[0442] (3)4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-pyhenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]-N-methylbenzamidetrifluoroacetate

[0443] NMR (DMSO-d₆, δ): 2.76 (3H, d, J=4.5 Hz), 2.86-4.30 (10H, m),5.41 (1H, br), 5.83 (1H, br), 6.94-7.00 (3H, m), 7.21 (2H, d, J=8.5 Hz),7.28-7.36 (2H, m), 7.44 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.8 Hz), 7.77(2H, d, J=8.8 Hz), 8.32 (2H, br), 8.69 (1H, br), 9.11 (1H, br s), 9.31(1H, br s) MS m/z: 493 (MH⁺)

[0444] (4)4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]-N-propylbenzamidetrifluoroacetate

[0445] NMR (DMSO-d₆, δ): 0.88 (3H, t, J=7.4 Hz), 1.43-1.58 (2H, m),2.80-4.20 (10H, m), 5.44 (1H, br), 5.86 (1H, br), 6.94-7.00 (3H, m),7.21 (2H, d, J=8.5 Hz), 7.28-7.36 (2H, m), 7.44 (2H, d, J=8.5 Hz), 7.51(2H, d, J=8.7 Hz), 7.78 (2H, d, J=8.7 Hz), 8.32 (2H, br), 8.92 (1H, br),9.08 (1H, br s), 9.28 (1H, br s)

[0446] MS m/z: 521 (MH⁺)

[0447] (5)4-[[[[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]-amino]-N,N-dimethylbenzamidetrifluroacetate

[0448] NMR (DMSO-d₆, δ): 2.61-3.65 (7H, m), 2.96 (6H, s), 3.96-4.00 (2H,m), 4.20 (1H, br) 5.32 (1H, br), 5.89 (1H, br), 6.94-7.00 (3H, m), 7.20(2H, d, J=8.5 Hz), 7.31 (2H, t, J=8.1 Hz), 7.35 (2H, d, J=8.7 Hz), 7.44(2H, d, J=8.5 Hz), 7.51 (2H, d, J=8.7 Hz), 8.32 (1H, br), 8.67 (1H, br),8.93 (1H, br s), 9.06 (1H, br s)

[0449] MS m/z: 507 (MH⁺)

EXAMPLE 34

[0450] To a solution ofN-[4-[(2S)-2-amino-3-hydroxypropyl]phenyl]-N′-phenylurea hydrochloride(222 mg) in ethanol (5.0 ml) were added successivelyN,N-diisopropylethylamine (264 μl) and(2S)-2-[[4-(benzyloxy)phenoxy)methyl]oxirane (212 mg) and the solutionwas refluxed for 13.5 hours. After cooling to room temperature, theprecipitates were collected by filtration, washed with ethanol, anddried under reduced pressure to giveN-[4-[(2S)-2-[[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea(166 mg) as a white solid.

[0451] MS m/z: 542 (MH⁺)

EXAMPLE 35

[0452]N-[4-[(2S)-2-[[(2S)-3-[4-(Benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea(159 mg) was dissolved in a mixed solvent of methanol (2.5 ml) and1,4-dioxane (2.5 ml) under heating. After cooling to room temperature,10% palladium on activated carbon (50% wet, 159 mg) was added and themixture was hydrogenated at 1 atm for 4 hours. The catalyst was removedby filtration and washed with methanol. The filtrate was concentrated invacuo to giveN-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino)propyl]phenyl]-N′-phenylurea(129 mg) as a white solid.

[0453] IR (KBr): 3456, 3296, 3033, 1643, 1595, 1560, 1511, 1442, 1230,1101, 1041, 827 cm⁻¹

[0454] NMR (DMSO-d₆, δ): 2.55-2.78 (5H, m), 3.23 (2H, br), 3.73-3.82(3H, m), 4.52 (1H, br), 4.89 (1H, br), 6.65 (2H, d, J=9.2 Hz), 6.74 (2H,d, J=9.2 Hz), 6.95 (1H, t-like, J=7.3 Hz), 7.09 (2H, d, J=8.4 Hz), 7.25(2H, d, J=8.3 Hz), 7.34 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=7.6 Hz), 8.57(1H, br), 8.63 (1H, br), 8.87 (1H, br)

[0455] MS m/z: 452 (MH⁺)

EXAMPLE 36

[0456] To a solution of(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl)amino)-1-propanol(300 mg) in 1,2-dichloroethane (3.0 ml) was addedN,O-bis(trimethylsilyl)acetamide (182 μl) and the solution was stirredat room temperature for 1 hour. To the solution were added successively4-(methoxycarbonyl)benzoic acid (160 mg), 1-hydroxybenzotriazole hydrate(120 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (170 mg) at room temperature. After stirring at the sametemperature for 3 hours, N,O-bis(trimethylsilyl)acetamide (182 μl) wasadded and the mixture was stirred overnight. The mixture was dilutedwith ethyl acetate (30 ml) and washed with a saturated aqueous sodiumbicarbonate solution (30 ml×1), water (30 ml×2) and brine (30 ml×1)successively, dried over magnesium sulfate, and evaporated to give ayellow solid. The solid was dissolved in tetrahydrofuran (3.0 ml). Tothe solution was added a 1.0 M solution of tetrabutylammonium fluoridein tetrahydrofuran (1.48 ml) at room temperature and the solution wasstirred for 10 minutes. The solution was diluted with ethyl acetate (20ml) and washed with water (20 ml×2) and brine (20 ml×1) successively,dried over magnesium sulfate, and evaporated to give a yellow solid. Thecrude product was purified by a recycling preparative high pressureliquid chromatography equipped with a gel permeation chromatographycolumn (eluent: chloroform) and silica gel chromatography (eluent:hexane/ethyl acetate=1/1) to give methyl4-[[[4-((2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]benzoate(132 mg) as a pale yellow solid.

[0457] MS m/z: 569 (MH⁺)

EXAMPLE 37

[0458] To a solution of methyl4-[((4-[((2S)-2-(N-benzyl-N-((2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]-phenyl]amino]carbonyl]benzoate(30.0 mg) in methanol (1.0 ml) was added 10% palladium on activatedcarbon (50% wet, 30 mg) and the mixture was hydrogenated at 1 atm for 2hours. The catalyst was filtered off and washed with methanol. Thefiltrate was concentrated in vacuo to give methyl4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-propyl]phenyl]amino]carbonyl]benzoate(21.9 mg) as a white solid.

EXAMPLE 38

[0459] To a suspension of methyl4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-amino]carbonyl]benzoate(19.3 mg) in methanol (1.0 ml) was added 1N sodium hydroxide solution(40.3 μl) and the suspension was refluxed for 10 hours. An additionalportion of 1N sodium hydroxide solution (40.3 μl) was added and themixture was refluxed for 3 hours. After cooling to room temperature, thesolvent was removed by evaporation to give sodium4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]benzoate(20.6 mg) as a white solid.

[0460] MS m/z: 487 (MH⁺)

EXAMPLE 39

[0461] To a solution of methyl4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]-phenyl]amino]carbonyl]benzoate(93.6 mg) in methanol (2.0 ml) was added 1N sodium hydroxide solution(329 μl) and the solution was refluxed for 2.5 hours. After cooling toroom temperature, the mixture was neutralized by the addition of 1Nhydrochloric acid (329 μl). The solvent was removed by evaporation andthe residual solid was suspended in water (2.0 ml). The solid wascollected by filtration, washed with water, and dried under reducedpressure to give4-[[[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]benzoicacid (80.2 mg) as a white solid.

[0462] MS (negative) m/z: 553 (M−H⁺)

EXAMPLE 40

[0463] To a solution of4-[[[4-((2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-amino)carbonyl]benzoicacid (14.6 mg) in N,N-dimethylformamide (200 μl) were added 1.0 Msolution of 1-hydroxybenzotriazole hydrate in N,N-dimethylformamide(31.6 l) and 1.0 M solution of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in 1,2-dichloroethane(31.6 μl) at room temperature. To the mixture was added methylaminehydrochloride (2.2 mg) and the whole was stirred overnight. The reactionmixture was diluted with ethyl acetate (10 ml) and washed with water (10ml×1) and brine (10 ml×1) successively, dried over magnesium sulfate,and evaporated to give a pale yellow paste. The crude product waspurified by a recycling preparative high pressure liquid chromatographyequipped with a gel permeation chromatography column (eluent:chloroform) to giveN¹-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]-phenyl]-N⁴-methylterephthalamide(14.0 mg) as a white solid.

EXAMPLE 41

[0464] The following compounds were obtained according to a similarmanner to that of Example 40.

[0465] (1)N¹-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N⁴,N⁴-dimethylterephthalamide

[0466] (2)N¹-[4-[(2S)-2-[N-Benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N⁴-propylterephthalamide

EXAMPLE 42

[0467] To a solution ofN¹-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]-N⁴-methylterephthalamide(14.0 mg) in methanol (0.5 ml) was added 10% palladium on activatedcarbon (50% wet, 14.0 mg) and the mixture was hydrogenated at 1 atm for3 hours. The catalyst was filtered off and washed with methanol. Thefiltrate was concentrated in vacuo to giveN¹-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]-phenyl]-N⁴-methylterephthalamide(9.7 mg) as a white solid.

[0468] MS m/z: 478 (MH⁺)

EXAMPLE 43

[0469] The following compounds were obtained according to a similarmanner to that of Example 42.

[0470] (1)N¹-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N⁴,N⁴-dimethylterephthalamide

[0471] MS m/z: 492 (MH⁺)

[0472] (2)N¹-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N⁴-propylterephthalamide

[0473] MS m/z: 505 (MH⁺)

EXAMPLE 44

[0474] To a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate(200 mg) in N,N-dimethylformamide (2.0 ml) was added successively1-methyl-1H-pyrrole-2-caroxylic acid (72.1 mg) and1-hydroxybenzotriazole hydrate (77.9 mg). To the mixture was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (110 mg)at room temperature and the mixture was stirred overnight. The mixturewas diluted with ethyl acetate (20 ml) and washed with water (20 ml×2),a saturated aqueous sodium hydrogencarbonate solution (20 ml×1) andbrine (20 ml×1) successively. The organic solution was dried overmagnesium sulfate, filtered, and evaporated to give a yellow solid. Thecrude product was purified by a recycling preparative high pressureliquid chromatography equipped with a gel permeation chromatographycolumn (eluent: chloroform) to give tert-butylN-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate(163 mg) as a white foam.

[0475] MS (ESI) m/z: 546 (M+Na⁺)

EXAMPLE 45

[0476] The following compounds were obtained according to a similarmanner to that of Example 44.

[0477] (1) tert-ButylN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[(2-phenoxy-3-pyridyl)carbonyl]amino]-benzyl]ethyl]carbamate

[0478] MS m/z: 636 (M+Na⁺)

[0479] (2) tert-ButylN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(8-quinolinylcarbonyl)amino]benzyl]-ethyl]carbamate

[0480] MS m/z: 594 (M+Na⁺)

[0481] (3) tert-ButylN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[[[5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl]carbonyl]amino]benzyl]ethyl]carbamate

[0482] MS m/z: 678 (M+Na⁺)

[0483] (4) tert-ButylN-[(1S)-2-hydroxy-1-[4-[[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

[0484] MS m/z: 623 (M+Na⁺)

[0485] (5) tert-ButylN-[(1S)-2-hydroxy-1-[4-[[(2-methyl-1H-benzimidazol-5-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl)carbamate

[0486] MS m/z: 597 (M+Na⁺)

[0487] (6) tert-ButylN-[(1S)-2-hydroxy-1-[4-[(1H-indol-5-ylcarbonyl)amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

[0488] MS m/z: 582 (M+Na⁺)

[0489] (7) tert-ButylN-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-indol-3-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate

[0490] MS m/z: 596 (M+Na⁺)

[0491] (8) tert-ButylN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(1H-pyrrol-3-ylcarbonyl)amino]-benzyl]ethyl]carbamate

[0492] MS m/z: 532 (M+Na⁺)

[0493] (9) tert-ButylN-[(2S)-2-hydroxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(1H-pyrrol-2-ylcarbonyl)amino]benzyl]-ethyl]carbamate

[0494] NMR (CDCl₃, δ): 1.46 (9H, s), 2.35-4.45 (10H, m), 6.21-6.36 (1H,m), 6.60-7.35 (9H, m), 7.51 (2H, d, J=8 Hz), 7.58 (1H, br s), 9.59 (1H,br s)

[0495] MS m/z: 532 (M⁺+Na)

EXAMPLE 46

[0496] tert-ButylN-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate(158 mg) was dissolved in 4N hydrogen chloride in ethanol (2.0 ml) andthe solution was stirred at room temperature for 2 hours. The solventwas removed by evaporation and the residual solid was dried underreduced pressure to giveN-[4-[(2S)-3-hydroxy-2-[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1-methyl-1H-pyrrole-2-carboxamidehydrochloride (125 mg) as a pale orange crystalline solid.

[0497] MS m/z: 424 (M+Na⁺)

EXAMPLE 47

[0498] The following compounds were obtained according to a similarmanner to that of Example 46.

[0499] (1)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-2-phenoxynicotinamidehydrochloride

[0500] MS m/z: 514 (MH⁺)

[0501] (2)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-8-quinolinecarboxamidedihydrochloride

[0502] MS m/z: 472 (MH⁺)

[0503] (3)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-5-[4-(trifluoromethyl)phenyl]-1,3-oxazole-4-carboxamidehydrochloride

[0504] MS m/z: 556 (M+Na⁺)

[0505] (4)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-5-methyl-1-phenyl-1H-pyrazole-4-carboxamidehydrochloride

[0506] MS m/z: 501 (M+Na⁺)

[0507] (5)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-2-methyl-1H-benzimidazole-5-carboxamidedihydrochloride

[0508] MS m/z: 475 (MH⁺)

[0509] (6)N-[4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1H-indole-5-carboxamidehydrochloride

[0510] MS m/z: 460 (M+Na⁺)

[0511] (7)N-[(4-[(2S)-3-Hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1-methyl-1H-indole-3-carboxamidehydrochloride

[0512] MS m/z: 474 (MH⁺)

EXAMPLE 48

[0513] To a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydoxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(120 mg) in N,N-dimethylformamide (2.0 ml) was added successively4-phenyl-1H-pyrrole-3-carboxylic acid (64.0 mg) and1-hydroxybenzotriazole hydrate (46.2 mg). To the mixture was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (65.6 mg)at room temperature and the mixture was stirred overnight. The mixturewas diluted with ethyl acetate (20 ml) and washed with water (20 ml×2),a saturated aqueous sodium hydrogencarbonate solution (20 ml×1) andbrine (20 ml×1) successively. The organic solution was dried overmagnesium sulfate, filtered, and evaporated to give a yellow solid. Thecrude product was purified by a recycling preparative high pressureliquid chromatography equipped with a gel permeation chromatographycolumn (eluent: chloroform) to give tert-butylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(4-phenyl-1H-pyrrol-3-yl)carbonyl]amino]benzyl]ethyl]carbamate(16 mg) as a yellow foam.

[0514] MS (ESI) m/z: 612 (M+Na⁺)

EXAMPLE 49

[0515] The following compounds were obtained according to a similarmanner to that of Example 48.

[0516] (1) tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-indol-5-yl)carbonyl]amino]benzyl]ethyl]carbamate

[0517] MS (ESI) m/z: 600 (M+Na⁺)

[0518] (2) Methyl4-[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]phenyl]amino]carbonyl]benzoate

[0519] MS m/z: 483 and 485 (MH⁺−100)

EXAMPLE 50

[0520] tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(4-phenyl-1H-pyrrol-3-yl)carbonyl]amino]benzyl]ethyl]carbamate(13.3 mg) was dissolved in 4N hydrogen chloride in ethanol (0.5 ml) andthe solution was stirred at room temperature for 5 hours. The solventwas removed by evaporation to giveN-[4-(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl)phenyl]-4-phenyl-1H-pyrrole-3-carboxyamidehydrochloride (12.8 mg) as a pale yellow solid.

[0521] MS m/z: 490 (MH⁺)

EXAMPLE 51

[0522] The following compounds were obtained according to a similarmanner to that of Example 50.

[0523] (1) Methyl4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]phenyl]amino]-carbonyl]benzoatehydrochloride

[0524] MS m/z: 483 (MH⁺)

[0525] (2)N-[4-[(2S)-3-Hydroxy-2-[[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1H-pyrrole-2-carboxamidehydrochloride

[0526] NMR (DMSO-d₆, δ) 2.70-3.75 (7H, m), 3.84-4.12 (2H, m), 4.12-4.40(1H, m), 5.41 (1H, m), 5.89 (1H, m), 6.16 (1H, m), 6.80-7.12 (5H, m),7.12-7.44 (4H, m), 7.72 (2H, d, J=8 Hz), 8.42 (1H, br s), 8.93 (1H, brs), 9.81 (1H, br s), 11.70 (1H, br s)

[0527] MS m/z: 410 (M⁺+1)

EXAMPLE 52

[0528] tert-ButylN-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-(4-[[(1-methyl-1H-indol-5-yl)carbonyl]amino]benzyl]ethyl]carbamate(101 mg) was dissolved in 4N hydrogen chloride in ethanol (1.0 ml) andthe solution was stirred at room temperature for 5 hours. The solventwas removed by evaporation and the residual solid was dissolved inmethanol. To the solution was added 1N sodium hydroxide solution (175μl) and the solvent was removed by evaporation. The residue waschromatographed on silica gel (eluent: chloroform/methanol=9/1) to giveN-[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]phenyl]-1-methyl-1H-indole-5-carboxamide(34.2 mg) as a pale yellow solid.

[0529] MS m/z: 478 (MH⁺)

EXAMPLE 53

[0530] To a suspension of methyl4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]-phenyl]amino]carbonyl]benzoatehydrochloride (101 mg) in methanol (4.0 ml) was added 1N sodiumhydroxide solution (486 μl) and the mixture was refluxed for 90 minutes.After cooling to room temperature, the solvent was removed byevaporation. The residual solid was applied on a solid phase extractioncartridge (BOND ELUT C18, 20 ml, VARIAN) and eluted with water andmethanol successively. The eluents containing the target compound werecombined and concentrated in vacuo to give sodium4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]-phenyl]amino]carbonyl]benzoate(66.7 mg) as an off-white solid.

[0531] MS m/z: 491 (MH⁺)

EXAMPLE 54

[0532] To a stirred suspension of(2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-1-propanol(51.3 mg), 1H-pyrrole-2-carboxylic acid (11.9 mg) and1-hydroxybenzotriazole hydrate (13.5 mg) in 1,2-dichloromethane (1.0 ml)was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(21.5 mg) under ice-cooling and the resulting mixture was stirred atroom temperature overnight. The mixture was diluted with saturatedaqueous sodium hydrogencarbonate solution and extracted twice with ethylacetate. The extracts were combined, washed twice with brine, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby preparative thin layer chromatography (eluent: toluen/ethylacetate=5/5) to giveN-[4-[(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]-amino]-3-hydroxypropyl]phenyl]-1H-pyrrole-2-carboxamide(43 mg) as a gum.

[0533] MS m/z: 606 (MH⁺)

EXAMPLE 55

[0534] To a solution ofN-[4-[(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]-phenyl]-1H-pyrrole-2-carboxamide(40 mg) in methanol (2.0 ml) was added 10% palladium on activated carbon(50% wet, 10 mg) and the mixture was hydrogenated at 1 atm for 3 hours.The catalyst was filtered off and washed with methanol. The filtrate wasconcentrated in vacuo and the residue was powdered from ether and driedto giveN-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]propyl]-phenyl]-1H-pyrrole-2-carboxamide(26 mg) as a gray powder.

[0535] MS m/z: 426 (MH⁺)

EXAMPLE 56

[0536] Under nitrogen, a solution of(S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]benzamide (60 mg) and(S)-4-(2-oxiranylmethoxy)carbazole (42.5 mg) in ethanol (10 ml) wasrefluxed for 18 hours. The mixture was evaporated in vacuo. The residuewas purified by column chromatography on silica gel(chloroform:methanol=100:1) to giveN-[4-[((2S)-2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]benzamide(50 mg) as a colorless foam.

[0537] IR (KBr): 3300-3000, 1725, 1650, 1602, 1511, 1446, 1259 cm⁻¹

[0538] NMR (MeOD-d₄, δ): 2.50-3.10 (4H, m), 3.20-3.70 (3H, m), 4.10-4.00(3H, m), 6.60 (1H, d, J=7.8 Hz), 7.05-8.00 (14H, m), 8.3 (1H, d, J=7.8Hz)

[0539] MS m/z: 510 (M+1)

EXAMPLE 57

[0540] The following compounds were obtained according to a similarmanner to that of Example 56.

[0541] (1)N-[4-[(2S)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]phenyl]benzamide

[0542] IR (KBr): 3500-3000, 1650, 1598, 1515, 1411, 1321, 1263 cm⁻¹

[0543] NMR (MeOD-d₄, δ): 2.70-3.20 (4H, m), 3.40-3.80 (3H, m), 4.70-4.80(1H, m), 7.10-7.70 (11H, m), 7.90-8.00 (2H, m)

[0544] MS m/z: 425 (M+1)

[0545] (2)N-[4-[(2S)-2-[[(2S)-3-(1H-Indoly-4-yloxy)-2-hydroxypropyl]amino]1-3-hydroxypropyl]phenyl]benzamide

[0546] IR (KBr): 3400-3000, 1658, 1646, 1598, 1513, 1444, 1241, 1091cm⁻¹

[0547] NMR (MeOD-d₄, δ): 2.70-3.20 (5H, m), 3.30-3.70 (2H, m), 4.00-4.25(3H, m), 6.40-6.60 (2H, m), 6.90-8.00 (12H, m)

[0548] MS m/z: 460 (M+1)

EXAMPLE 58

[0549] In 4N hydrogen chloride in ethanol (2.0 ml), tert-butylN-[(2S)-2-hydoxy-3-phenoxypropyl]-N-[(1S)-2-hydroxy-1-[4-[(1H-pyrrol-3-ylcarbonyl)amino]benzyl]ethyl]carbamate(113.5 mg) was dissolved and the solution was stirred at roomtemperature for 30 hours. After concentration under reduced pressure,the residue was extracted with ethyl acetate (20 ml) and washed withsaturated sodium hydrogencarbonate aqueous solution (20 ml). The organiclayer was separated and the aqueous layer was extracted twice with ethylacetate (20 ml). The organic layers were combined and washed with brine,and dried over magnesium sulfate to giveN-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]-phenyl]-1H-pyrrole-3-carboxamide(18.2 mg) as a yellow solid.

[0550] MS m/z: 410 (MH⁺), 432 (M+Na⁺)

EXAMPLE 59

[0551] Step 1: Preparation of Polymer-Bound HOBt ester (1)

[0552] Polystyrene-bound 1-hydroxybenzotriazole (HOBt),bis-(6-carboxy-HOBt)-N-(2-aminoethyl)aminomethyl polystyrene (200 mg,1.54 mmole/g, Novabiochem) was added to a 6 ml polypropylene tube(Varian). A solution of a carboxylic acid derivative (

[0553] or hydrochloride thereof corresponding to an objective amidederivative in N,N-dimethylformamide (DMF) (0.4 M, 2.3 ml) was added tothe tube and shaken for 5 minutes. To the reaction mixture was added1,3-diisopropylcarbodiimide (72.4 μl) and shaken for 3 hours at ambienttemperature. The resin was filtered and washed well with DMF. Anadditional 2.3 ml of 0.4 M carboxylic acid derivative solution in DMFand 1,3-diisopropylcarbodiimide (72.4 μl) were added and shaken for 3hours at ambient temperature. The resultant resin was filtered, washedwell subsequently with DMF, dichloromethane (DCM), diethyl ether, anddried under reduced pressure to give polymer-bound HOBt ester (1).

[0554] Step 2: General Procedure for the Amide Derivatives (2)

[0555] To a 6 ml polypropylene tube (Varian) was added 0.024 M solutionof tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamatein DCM (1 ml) and N,O-bis(trimethylsilyl)acetamide (18 μl). Aftershaking for 30 minutes, polymer-bound HOBt ester (100 mg) was added tothe reaction mixture and shaken overnight at ambient temperature. Thepolymer was filtered, washed well with DCM and concentrated underreduced pressure. To the resultant residue was added 1 ml of 50%trifluoroacetic acid (TFA) in DCM and shaken for 3 hours at ambienttemperature. The solvent was evaporated and purified by HPLC (reversephase C₁₈, 0-80% 0.1% TFA in acetonitrile/0.1% TFA in water. Thefractions containing the desired compound were combined, evaporated anddried under reduced pressure to give the objective amide derivative (2).

[0556] Following the Steps 1 and 2 outlined above, the compounds listedin Table 1 were obtained. TABLE 1

•pCF₃CO₂H (p = 1 or 2) Example B p MS [M + H]⁺ Data 59-(1)

1 455 59-(2)

1 411 59-(3)

1 437 59-(4)

1 481 59-(5)

1 411 59-(6)

1 427 59-(7)

1 427 59-(8)

1 460 59-(9)

1 477 59-(10)

2 450 59-(11)

2 473 59-(12)

1 451 59-(13)

1 475

EXAMPLE 60

[0557] General Procedure for the Amide Derivatives (3)

[0558] To a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-[(trimethylsilyl)oxy]ethyl]-N-[(2S)-3-phenoxy-2-[(trimethylsilyl)oxy]propyl]carbamatein N,N-dimethylformamide (DMF) (0.059 M, 300 μl) was added a carboxylicacid derivative (

[0559] or hydrochloride thereof) corresponding to an objective amidederivative (21.4 μM) and a solution ofbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate in DMF(0.142 M, 150 μl). After shaking for 5 minutes, to the reaction mixturewas added N,N-diisopropylethylamine (DIEA, 7.8 μl) and shaken overnightat ambient temperature. In the case that 3-pyridylacetic acid was usedas a carboxylic acid derivative, additional 15.6 μl of DIEA was added tothe reaction mixture. The reaction mixture was loaded onto thesolid-phase extraction cartridge (Waters, Oasis) conditioned usingacetonitrile (CH₃CN, 6 ml) and water (6 ml), washed with water (6 ml)and 10% CH₃CN in water (6 ml), and eluted with CH₃CN (6 ml). Evaporationof the solvent gave a residue, to which was added 50% trifluoroaceticacid in dichloromethane (DCM) (1 ml) and shaken for 3 hours at ambienttemperature. Evaporation of the solvent gave a residue, which waspurified by HPLC (reverse phase C₁₈, 0-80% 0.1% TFA in CH₃CN/0.1% TFA inwater). The fractions containing the desired compound were combined,evaporated and dried under reduced pressure to give the objective amidederivative (3).

[0560] Following the procedure outlined above, the compounds listed inTable 2 were obtained. TABLE 2

•pCF₃CO₂H (p = 1 or 2) Example B p MS [M + H]⁺ Data 60-(1)

1 422 60-(2)

1 474 60-(3)

1 427 60-(4)

1 457 60-(5)

2 436 60-(6)

2 422 60-(7)

1 472 60-(8)

1 472 60-(9)

2 411 60-(10)

1 460 60-(11)

1 461 60-(12)

1 486 60-(13)

1 475 60-(14)

1 474 60-(15)

1 435 60-(16)

1 435 60-(17)

1 435 60-(18)

1 439 60-(19)

1 439 60-(20)

1 439 60-(21)

1 466 60-(22)

1 466 60-(23)

1 466 60-(24)

1 489 60-(25)

1 489 60-(26)

1 489

EXAMPLE 61

[0561] General Procedure for the Amide Derivatives (4)

[0562] Method A

[0563] To a solution of a carboxylic acid derivative

[0564] corresponding to an objective amide derivative (0.024 mmol) inNMP (36 μl) was added 1.0 M solution of N,O-bis(trimethylsilyl)acetamide(BSA) in N-methyl-2-pyrrolidinone (NMP) (12 μl, 0.012 mmol). Aftershaking for 30 minutes at room temperature, 1.0 M solution ofN,N-diisopropylethylamine (DIEA) in NMP (50 μl, 0.05 mmol) and 0.5 Msolution of benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate in NMP (60 μl, 0.03 mmol) were added to the solutionand the mixture was shaken for 30 minutes at room temperature. Inanother vessel, a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(0.02 mmol) in NMP (20 μl) and 1.0 M solution of BSA in NMP (20 μl, 0.02mmol) was shaken for 30 minutes at room temperature, and the solutionwas added to the above activated ester solution. The mixture was allowedto warm to 50° C. and shaken for 2 hours. After cooling to roomtemperature, 0.5 ml of 95% trifluoroacetic acid (TFA) in water was addedto the solution and shaken for 15 hours. The mixture was concentratedunder reduced pressure and purified by HPLC (reverse phase C₁₈, 0-80%0.1% TFA in acetonitrile (CH₃CN)/0.1% TFA in water. The fractionscontaining the desired compound were combined, concentrated and driedunder reduced pressure to give the objective amide derivative (4).

[0565] Method B

[0566] To a solution of a carboxylic acid derivative (

[0567] or hydrochloride thereof) corresponding to an objective amidederivative (0.024 mmol) in NMP (36 μl) was added 1.0 M solution of BSAin NMP (12 l, 0.012 mmol). After shaking for 30 minutes at roomtemperature, 0.5 M solution of 1-hydroxybenzotriazole (HOBt) in NMP (60μl, 0.03 mmol) and 0.5 M solution of 1-ethyl3-(3′-dimethylaminopropyl)carbodiimide (EDC) in NMP (60 μl, 0.03 mmol)were added to the solution and the mixture was shaken for 30 minutes atroom temperature. In another vessel, a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(0.02 mmol) in NMP (20 μl) and 1.0 M solution of BSA in NMP (20 μl, 0.02mmol) was shaken for 30 minutes at room temperature, and the solutionwas added to the above activated ester solution. The mixture was allowedto warm to 50° C. and shaken for 15 hours. After cooling to roomtemperature, 0.5 ml of 95% TFA in water was added to the solution andshaken for 15 hours. The mixture was concentrated under reduced pressureand purified by HPLC (reverse phase C₁₈, 0-80% 0.1%, TFA in CH₃CN/0.1%TFA in water). The fractions containing the desired compound werecombined, concentrated and dried under reduced pressure to give theobjective amide derivative (4).

[0568] Following Method A or Method B outlined above, the compoundslisted in Table 3 were obtained. TABLE 3

•CF₃CO₂H Example B MS [M + H]⁺ Data Method 61-(1)

426, 428 A 61-(2)

427, 429 A 61-(3)

431, 433 A 61-(4)

415, 416 A 61-(5)

475 A 61-(6)

476, 477 A 61-(7)

476, 477 A 61-(8)

476 A 61-(9)

476, 477 A 61-(10)

477, 478 A 61-(11)

585, 586 A 61-(12)

428 A 61-(13)

518 A 61-(14)

455 A 61-(15)

455 A 61-(16)

455, 456 A 61-(17)

426 A 61-(18)

426 A 61-(19)

431 A 61-(20)

415 A 61-(21)

522, 523 A 61-(22)

476, 478 A 61-(23)

476 A 61-(24)

475, 476 A 61-(25)

476, 477 A 61-(26)

478 A 61-(27)

506 A 61-(28)

495 A 61-(29)

459, 461 A 61-(30)

459, 461 A 61-(31)

459 A 61-(32)

478, 479 A 61-(33)

414 B 61-(34)

464 B 61-(35)

464, 465 B 61-(36)

478 B 61-(37)

478 B 61-(38)

481, 482 B 61-(39)

466 B 61-(40)

482, 484 B 61-(41)

506, 507 A 61-(42)

477 A 61-(43)

414 B 61-(44)

490, 491 B

EXAMPLE 62

[0569] General Procedure for the Amide Derivatives (5)

[0570] A mixture of a carboxylic acid derivative

[0571] corresponding to an objective amide derivative (0.024 mmol) and1.0 M pyridine in 1,2-dichloroethane (DCE) (24 μl) was treated with 1.0M solution of oxallyl chloride in DCE (26 μl) at room temperature. Afterstirring for 1 hour, the mixture was diluted withN-methyl-2-pyrrolidinone (NMP) (20 μl). To a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-hydroxy-3-phenoxypropyl]carbamate(0.02 mmol) in NMP (20 μl) was added 1.0 M solution ofN,O-bis(trimethylsilyl)acetamide (BSA) in NMP (20 μl, 0.02 mmol), andthe solution was stirred at room temperature. After stirring for 30minutes, the solution was added to the acid chloride solution. Afterfurther stirring at 50° C. for 30 minutes, the reaction mixture wastreated with 95% trifluoroacetic acid (TFA) in water (500 μl) at 50° C.for 30 minutes. The mixture was concentrated under reduced pressure andthe residue was purified by HPLC (reverse phase C₁₈, 0-80% 0.1% TFA inacetonitrile/0.1% TFA in water). The fractions containing the desiredcompound were combined, concentrated and dried under reduced pressure togive the objective amide derivative (5).

[0572] Following the procedure outlined above, the compounds listed inTable 4 were obtained. TABLE 4

•CF₃CO₂H Example B MS [M + H]⁺ Data 62-(1)

565 62-(2)

460 62-(3)

440 62-(4)

526 62-(5)

497 62-(6)

456 62-(7)

512 62-(8)

488 62-(9)

498 62-(10)

487 62-(11)

514 62-(12)

488 62-(13)

486 62-(14)

487 62-(15)

497 62-(16)

497

EXAMPLE 63

[0573] General Procedure for the Amide Derivatives (6)

[0574] The amide derivatives above were obtained according to a similarmanner to that of Example 62 using tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamateinstead of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-hydroxy-3-phenoxypropyl]carbamate.

[0575] Following the procedure outlined above, the compounds listed inTable 5 were obtained. TABLE 5

•CF₃CO₂H Example B MS [M + H]⁺ Data 63-(1)

570 63-(2)

464 63-(3)

506 63-(4)

444 63-(5)

531 63-(6)

502 63-(7)

460 63-(8)

516 63-(9)

493 63-(10)

503 63-(11)

491 63-(12)

518 63-(13)

490 63-(14)

492 63-(15)

502 63-(16)

502 63-(17)

560

EXAMPLE 64

[0576] General Procedure for the Urea Derivatives (7)

[0577] To a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-hydroxy-3-phenoxypropyl]carbamate(0.02 mmol) in N-methyl-2-pyrrolidinone (NMP) (40 μl) was added 2.0 Msolution of N,O-bis(trimethylsilyl)acetamide (BSA) in NMP (10 pl, 0.02mmol) at room temperature. After stirring for 30 minutes, 1.0 M solutionof an isocyanate derivative (O═C=N-B) corresponding to an objective ureaderivative in NMP (24 pl, 0.024 mmol) and 0.1 M solution ofN,N-diisopropylethylamine (DIEA) in NMP (20 μl, 0.002 mmol) were addedto the solution. After further stirring at 50° C. for 30 minutes, thereaction mixture was treated with 95% trifluoroacetic acid (TFA) inwater (500 μl) at 50° C. for 30 minutes. The mixture was concentratedunder reduced pressure and the residue was purified by HPLC (reversephase C₁₈, 0-80% 0.1% TFA in acetonitrile/0.1% TFA in water). Thefractions containing the desired compound were combined, concentratedand dried under reduced pressure to give the objective urea derivative(7).

[0578] Following the procedure outlined above, the compounds listed inTable 6 were obtained. TABLE 6

•CF₃CO₂H Example B MS [M + H]⁺ Data 64-(1)

450 64-(2)

470 64-(3)

515 64-(4)

466 64-(5)

504 64-(6)

512 64-(7)

512 64-(8)

528 64-(9)

528 64-(10)

528 64-(11)

520 64-(12)

520 64-(13)

486 64-(14)

486 64-(15)

505 64-(16)

505 64-(17)

505

EXAMPLE 65

[0579] General Procedure for the Amide Derivatives (8)

[0580] The amide derivatives above were obtained according to a similarmanner to that of Example 64 using an acyl chloride derivative

[0581] instead of an isocyanate derivative (O═C═N—B).

[0582] Following the procedure above, the compounds listed in Table 7were obtained. TABLE 7

•CF₃CO₂H Example X₃—B MS [M + H]⁺ Data 65-(1)

450 65-(2)

428

EXAMPLE 66

[0583] General Procedure for the Urea Derivatives (9)

[0584] To a solution of tert-butylN-[(1s)-1-(4-aminobenzyl)-2-hydroxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-carbamate(0.02 mmol) in NMP (40 ul) was added 2.0 M solution ofN,O-bis(trimethylsilyl)acetamide (BSA) in N-methyl-2-pyrrolidinone (NMP)(10 μl, 0.02 mmol) and the mixture was shaken for 30 minutes at roomtemperature. To the solution, 1.0 M solution of an isocyanate derivative(O═C═N—B) corresponding to an objective urea derivative in NMP (24 μl,0.024 mmol) and 0.1 M solution of N,N-diisopropylethylamine (DIEA) inNMP (20 μl, 0.002 mmol) were added and the mixture was shaken for 30minutes at 50° C. After cooling to room temperature, 0.5 ml of 95%trifluoroacetic acid (TFA) in water was added to the solution and shakenfor 15 hours. The mixture was concentrated under reduced pressure andpurified by HPLC (reverse phase C₁₈, 0-80% 0.1% TFA in acetonitrile/0.1%TFA in water). The fractions containing the desired compound werecombined, concentrated and dried under reduced pressure to give theobjective urea derivative (9).

[0585] Following the procedure outlined above, the compounds listed inTable 8 were obtained. TABLE 8

•CF₃CO₂H Example B MS [M + H]⁺ Data 66-(1)

474 66-(2)

474 66-(3)

474 66-(4)

470 66-(5)

470 66-(6)

470 66-(7)

406, 408 66-(8)

406 66-(9)

454, 456

EXAMPLE 67

[0586] General Procedure for the Amide Derivatives (10)

[0587] The amide derivatives above were obtained according to a similarmanner to that of Example 66 using an acyl chloride derivative

[0588] corresponding to an objective amide derivative instead of anisocyanate derivative (O═C═N—B).

[0589] Following the procedure above, the compounds listed in Table 9were obtained. TABLE 9

•CF₃CO₂H Example X₃—B MS [M + H]⁺ Data 67-(1)

454 67-(2)

432

EXAMPLE 68

[0590] General Procedure for the Urea Derivatives (11)

[0591] To a 0.5 M solution of an amine derivative (_(H) ^(HN-B))corresponding to an objective urea derivative inN-methyl-2-pyrrolidinone (NMP) (50μ, 0.025 mmol) was added 1.0 Msolution of 1,1′-carbonyldiimidazole (CDI) (26.3 μl, 0.0263 mmol) andthe mixture was shaken for 30 minutes at room temperature. In anothervessel, a solution of tert-butylN-[(1S)-1-(4-aminobenzyl)-2-hydroxyethyl-3-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate(0.02 mmol) in NMP (20 μl) and 1.0 M solution ofN,O-bis(trimethylsilyl)-acetamide (BSA) in NMP (20 μl, 0.02 mmol) wasshaken for 30 minutes at room temperature, and the solution was added tothe above solution. After shaking for 2 hours, 0.5 ml of 95%trifluoroacetic acid (TFA) in water was added to the solution and shakenfor 15 hours. The mixture was concentrated under reduced pressure andpurified by HPLC (reverse phase C₁₈, 0-80% 0.1% TFA in acetonitrile/0.1%TFA in water). The fractions containing the desired compound werecombined, concentrated and dried under reduced pressure to give theobjective urea derivative (11).

[0592] Following the procedure outlined above, the compounds listed inTable 10 were obtained. TABLE 10

Example B MS [M + H]⁺ Data 68-(1)

446 68-(2)

441, 442 68-(3)

491, 492 68-(4)

491 68-(5)

491, 493 68-(6)

491, 493 68-(7)

491, 492

1. A compound of the general formula [I]:

wherein X₁ is bond or —O—CH₂—,

(in which R² is hydrogen or lower alkyl and n is an integer of 1 or 2)(in which R³ is hydrogen or lower alkyl),

(in which R⁴ is hydrogen or lower

—CH₂CH₂—, —CH═CH— or (in which Y₂ is lower alkylene)], R¹ is hydrogen oran amino protective group, A is phenyl, indolyl or carbazolyl, each ofwhich may be substituted with one or two substituent(s) selected fromthe group consisting of halogen, hydroxy, hydroxy(lower)alkyl andbenzyloxy, and B is hydrogen; halogen; lower alkyl; loweralkoxycarbonyl; cyclo(lower)alkyl; or a heterocyclic group, naphthyl,1,2,3,4-tetrahydronaphthyl, benzyl or phenyl, each of which may besubstituted with one or two substituent(s) selected from the groupconsisting of halogen, lower alkoxy, mono(or di ortri)halo(lower)alkoxy, carboxy(lower)alkoxy, loweralkoxycarbonyl(lower)alkoxy, phenoxy, lower alkyl, mono(or di ortri)halo(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, loweralkanoyl, benzoyl, mono(or di)(lower)alkylcarbamoyl, (loweralkylsulfonyl)carbamoyl, (lower alkylsulfonyl)-amino, (loweralkoxycarbonyl)amino, amino, nitro, pyridyl, triazolyl, thiazolyloptionally substituted with phenyl or lower alkyl, and phenyl optionallysubstituted with mono(or di or tri)halo(lower)alkyl, or a salt thereof.2. A compound of claim 1, wherein X₁ is bond or —O—CH₂—,

(in which R² is hydrogen or lower alkyl and n is an integer of 1 or 2)[in which

(in which R³ is hydrogen or lower alkyl),

(in which R⁴ is hydrogen or lower

—CH₂CH₂—, —CH═CH— or (in which Y₂ is lower alkylene)], R¹ is hydrogen, Ais phenyl which may be substituted with one or two substituent(s)selected from the group consisting of halogen, hydroxy,hydroxy(lower)alkyl and benzyloxy, B is pyrrolyl, imidazolyl, pyrazolyl,pyridyl, pyrazinyl, piperidyl, indolyl, benzimidazolyl, quinolyl,isoquinolyl, quinoxalinyl, cinnolinyl, indazolyl, oxazolyl, isoxazolyl,thiazolyl, thienyl, furyl, benzofuranyl, benzothienyl, naphthyl, benzylor phenyl, each of which may be substituted with one or twosubstituent(s) selected from the group consisting of halogen, loweralkoxy, mono(or di or tri)halo(lower)alkoxy, carboxy(lower)alkoxy, loweralkoxycarbonyl-(lower)alkoxy, phenoxy, lower alkyl, mono(or di ortri)halo(lower)alkyl, cyano, carboxy, lower alkoxycarbonyl, loweralkanoyl, benzoyl, mono(or di)(lower)alkylcarbamoyl, (loweralkylsulfonyl)-carbamoyl, (lower alkylsulfonyl)amino, (loweralkoxycarbonyl)amino, amino, nitro, pyridyl, triazolyl, thiazolyloptionally substituted with phenyl or lower alkyl, and phenyl optionallysubstituted with mono(or di or tri)halo(lower)alkyl.
 3. A compound ofclaim 2, wherein X₁ is —O—CH₂—,

(in which R² is hydrogen and n is an integer of 1) or R¹ is hydrogen, Ais phenyl which may be substituted with one or two substituent(s)selected from the group consisting of halogen, hydroxy,hydroxy(lower)alkyl and benzyloxy, B is pyrrolyl, pyridyl, naphthyl orphenyl, each of which may be substituted with one or two substituent(s)selected from the group consisting of halogen, lower alkoxy,carboxy(lower)alkoxy, lower alkoxycarbonyl(lower)alkoxy, lower alkyl,mono(or di or tri)halo(lower)alkyl, cyano, carboxy, loweralkoxycarbonyl, lower alkanoyl, mono(or di)(lower)alkylcarbamoyl, (loweralkylsulfonyl)carbamoyl, (lower alkylsulfonyl) amino, (loweralkoxycarbonyl) amino and nitro.
 4. A compound of claim 3, which is (1)N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1H-pyrrole-2-carboxamide;(2)N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-phenylurea;(3)N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1-naphthamide;(4)N-(3-fluorophenyl)-N′-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]urea;(5)N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-N′-(3-methoxyphenyl)urea,or a salt thereof.
 5. A process for preparing a compound of claim 1, ora salt thereof, which comprises, (i) reacting a compound [II] of theformula:

wherein X₁ and A are each as defined in claim 1, or a salt thereof, witha compound [III] of the formula:

wherein X₂, R¹ and B are each as defined in claim 1, or a salt thereof,to give a compound [I] of the formula:

wherein X₁, X₂, R1, A and B are each as defined in claim 1, or a saltthereof, or (ii) subjecting a compound [Ia] of the formula:

wherein X₁, X₂, A and B are each as defined in claim 1, and βR_(a) ¹ isan amino protective group, or a salt thereof, to elimination reaction ofthe amino protective group, to give a compound [Ib] of the formula:

wherein X₁, X₂, A and B are each as defined in claim 1, or a saltthereof, or (iii) reacting a compound [IV] of the formula:

wherein X₁, R¹ and A are each as defined in claim 1, or a salt thereof,with a compound [V] of the formula:

wherein B is as defined in claim 1, and W₁ is a leaving group, or a saltthereof, to give a compound [Ic] of the formula:

wherein X¹, R¹, A and B are each as defined in claim 1, or a saltthereof, or (iv) reacting a compound [Id] of the formula:

wherein X₁, R¹, A and B are each as defined in claim 1, and m is aninteger of 1 or 2, or a salt thereof, with a compound [VI] of theformula: W₂—R²  [VI] wherein R_(a) ² is lower alkyl, and W₂ is an acidresidue, to give a compound [Ie] of the formula:

wherein X₁, R¹, A and B are each as defined in claim 1, R_(a) ² is loweralkyl, and m is an integer of 1 or 2, or a salt thereof, and (v)reacting a compound [IV] of the formula:

wherein X₁, R¹ and A are each as defined in claim 1, or a salt thereof,with a compound [VII] of the formula:

wherein B is as defined in claim 1, and k is 0 or an integer of 1, or asalt thereof, to give a compound [If] of the formula:

wherein X₁, R¹, A and B are each as defined in claim 1, and k is 0 or aninteger of 1, or a salt thereof.
 6. A pharmaceutical composition whichcomprises, as an active ingredient, a compound of claim 1 or apharmaceutically acceptable salt thereof in admixture withpharmaceutically acceptable carriers or excipients.
 7. Use of a compoundof claim 1 or a pharmaceutically acceptable salt thereof for themanufacture of a medicament.
 8. A compound of claim 1 or apharmaceutically acceptable salt thereof for use as a medicament.
 9. Amethod for the prophylactic and/or therapeutic treatment of pollakiuria,urinary incontinence, obesity or diabetes, which comprises administeringa compound of claim 1 or a pharmaceutically acceptable salt thereof to ahuman being or an animal.